Publications by authors named "Jill L Silverman"

54 Publications

Sex-specific acute and chronic neurotoxicity of acute diisopropylfluorophosphate (DFP)-intoxication in juvenile Sprague-Dawley rats.

Curr Res Toxicol 2021 14;2:341-356. Epub 2021 Sep 14.

Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA.

Preclinical efforts to improve medical countermeasures against organophosphate (OP) chemical threat agents have largely focused on adult male models. However, age and sex have been shown to influence the neurotoxicity of repeated low-level OP exposure. Therefore, to determine the influence of sex and age on outcomes associated with acute OP intoxication, postnatal day 28 Sprague-Dawley male and female rats were exposed to the OP diisopropylfluorophosphate (DFP; 3.4 mg/kg, s.c.) or an equal volume of vehicle (∼80 µL saline, s.c.) followed by atropine sulfate (0.1 mg/kg, i.m.) and pralidoxime (2-PAM; 25 mg/kg, i.m.). Seizure activity was assessed during the first 4 h post-exposure using behavioral criteria and electroencephalographic (EEG) recordings. At 1 d post-exposure, acetylcholinesterase (AChE) activity was measured in cortical tissue, and at 1, 7, and 28 d post-exposure, brains were collected for neuropathologic analyses. At 1 month post-DFP, animals were analyzed for motor ability, learning and memory, and hippocampal neurogenesis. Acute DFP intoxication triggered more severe seizure behavior in males than females, which was supported by EEG recordings. DFP caused significant neurodegeneration and persistent microglial activation in numerous brain regions of both sexes, but astrogliosis occurred earlier and was more severe in males compared to females. DFP males and females exhibited pronounced memory deficits relative to sex-matched controls. In contrast, acute DFP intoxication altered hippocampal neurogenesis in males, but not females. These findings demonstrate that acute DFP intoxication triggers seizures in juvenile rats of both sexes, but the seizure severity varies by sex. Some, but not all, chronic neurotoxic outcomes also varied by sex. The spatiotemporal patterns of neurological damage suggest that microglial activation may be a more important factor than astrogliosis or altered neurogenesis in the pathogenesis of cognitive deficits in juvenile rats acutely intoxicated with OPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.crtox.2021.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8484742PMC
September 2021

Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome.

Neurotherapeutics 2021 Sep 15. Epub 2021 Sep 15.

School of Medicine, Department of Psychiatry and Behavioral Sciences, MIND Institute, University of California, Research II Building 96, 4625 2nd Avenue, Suite 1001B, Davis, Sacramento, CA, 95817, USA.

Angelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11-13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13311-021-01082-xDOI Listing
September 2021

Insulin-like growth factor-2 does not improve behavioral deficits in mouse and rat models of Angelman Syndrome.

Mol Autism 2021 09 15;12(1):59. Epub 2021 Sep 15.

MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.

Background: Angelman Syndrome (AS) is a rare neurodevelopmental disorder for which there is currently no cure or effective therapeutic. Since the genetic cause of AS is known to be dysfunctional expression of the maternal allele of ubiquitin protein ligase E3A (UBE3A), several genetic animal models of AS have been developed. Both the Ube3a maternal deletion mouse and rat models of AS reliably demonstrate behavioral phenotypes of relevance to AS and therefore offer suitable in vivo systems in which to test potential therapeutics. One promising candidate treatment is insulin-like growth factor-2 (IGF-2), which has recently been shown to ameliorate behavioral deficits in the mouse model of AS and improve cognitive abilities across model systems.

Methods: We used both the Ube3a maternal deletion mouse and rat models of AS to evaluate the ability of IGF-2 to improve electrophysiological and behavioral outcomes.

Results: Acute systemic administration of IGF-2 had an effect on electrophysiological activity in the brain and on a metric of motor ability; however the effects were not enduring or extensive. Additional metrics of motor behavior, learning, ambulation, and coordination were unaffected and IGF-2 did not improve social communication, seizure threshold, or cognition.

Limitations: The generalizability of these results to humans is difficult to predict and it remains possible that dosing schemes (i.e., chronic or subchronic dosing), routes, and/or post-treatment intervals other than that used herein may show more efficacy.

Conclusions: Despite a few observed effects of IGF-2, our results taken together indicate that IGF-2 treatment does not profoundly improve behavioral deficits in mouse or rat models of AS. These findings shed cautionary light on the potential utility of acute systemic IGF-2 administration in the treatment of AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13229-021-00467-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444390PMC
September 2021

Persistent neuropathology and behavioral deficits in a mouse model of status epilepticus induced by acute intoxication with diisopropylfluorophosphate.

Neurotoxicology 2021 Sep 9;87:106-119. Epub 2021 Sep 9.

Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA, 95616, USA; MIND Institute, School of Medicine, University of California, Davis, Sacramento, CA, 95817, USA. Electronic address:

Organophosphate (OP) nerve agents and pesticides are a class of neurotoxic compounds that can cause status epilepticus (SE), and death following acute high-dose exposures. While the standard of care for acute OP intoxication (atropine, oxime, and high-dose benzodiazepine) can prevent mortality, survivors of OP poisoning often experience long-term brain damage and cognitive deficits. Preclinical studies of acute OP intoxication have primarily used rat models to identify candidate medical countermeasures. However, the mouse offers the advantage of readily available knockout strains for mechanistic studies of acute and chronic consequences of OP-induced SE. Therefore, the main objective of this study was to determine whether a mouse model of acute diisopropylfluorophosphate (DFP) intoxication would produce acute and chronic neurotoxicity similar to that observed in rat models and humans following acute OP intoxication. Adult male C57BL/6J mice injected with DFP (9.5 mg/kg, s.c.) followed 1 min later with atropine sulfate (0.1 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.) developed behavioral and electrographic signs of SE within minutes that continued for at least 4 h. Acetylcholinesterase inhibition persisted for at least 3 d in the blood and 14 d in the brain of DFP mice relative to vehicle (VEH) controls. Immunohistochemical analyses revealed significant neurodegeneration and neuroinflammation in multiple brain regions at 1, 7, and 28 d post-exposure in the brains of DFP mice relative to VEH controls. Deficits in locomotor and home-cage behavior were observed in DFP mice at 28 d post-exposure. These findings demonstrate that this mouse model replicates many of the outcomes observed in rats and humans acutely intoxicated with OPs, suggesting the feasibility of using this model for mechanistic studies and therapeutic screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuro.2021.09.001DOI Listing
September 2021

Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in the Deletion Rat Model of Angelman Syndrome.

J Neurosci 2021 Oct 2;41(42):8801-8814. Epub 2021 Sep 2.

MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, California 95817

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50 kHz ultrasonic emissions in the rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying LTP deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared with currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS. Angelman syndrome (AS) is a severe neurogenetic disorder for which there is no cure, despite decades of research using mouse models. This study used a recently developed rat model of AS to delineate disease-relevant outcome measures to facilitate therapeutic development. We found the rat to be a strong model of AS, offering several advantages over mouse models by exhibiting numerous AS-relevant phenotypes, including overabundant laughter-like vocalizations, reduced hippocampal LTP, and volumetric anomalies across the brain. These findings are unconfounded by detrimental motor abilities and background strain, issues plaguing mouse models. This rat model represents an important advancement in the field of AS, and the outcome metrics reported herein will be central to the therapeutic pipeline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0925-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528495PMC
October 2021

Sexually dimorphic neuroanatomical differences relate to ASD-relevant behavioral outcomes in a maternal autoantibody mouse model.

Mol Psychiatry 2021 Jul 21. Epub 2021 Jul 21.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA.

Immunoglobulin G (IgG) autoantibodies reactive to fetal brain proteins in mothers of children with ASD have been described by several groups. To understand their pathologic significance, we developed a mouse model of maternal autoantibody related ASD (MAR-ASD) utilizing the peptide epitopes from human autoantibody reactivity patterns. Male and female offspring prenatally exposed to the salient maternal autoantibodies displayed robust deficits in social interactions and increased repetitive self-grooming behaviors as juveniles and adults. In the present study, neuroanatomical differences in adult MAR-ASD and control offspring were assessed via high-resolution ex vivo magnetic resonance imaging (MRI) at 6 months of age. Of interest, MAR-ASD mice displayed significantly larger total brain volume and of the 159 regions examined, 31 were found to differ significantly in absolute volume (mm) at an FDR of <5%. Specifically, the absolute volumes of several white matter tracts, cortical regions, and basal nuclei structures were significantly increased in MAR-ASD animals. These phenomena were largely driven by female MAR-ASD offspring, as no significant differences were seen with either absolute or relative regional volume in male MAR-ASD mice. However, structural covariance analysis suggests network-level desynchronization in brain volume in both male and female MAR-ASD mice. Additionally, preliminary correlational analysis with behavioral data relates that volumetric increases in numerous brain regions of MAR-ASD mice were correlated with social interaction and repetitive self-grooming behaviors in a sex-specific manner. These results demonstrate significant sex-specific effects in brain size, regional relationships, and behavior for offspring prenatally exposed to MAR-ASD autoantibodies relative to controls.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-021-01215-wDOI Listing
July 2021

The Effects of Chronic Exposure to Ambient Traffic-Related Air Pollution on Alzheimer's Disease Phenotypes in Wildtype and Genetically Predisposed Male and Female Rats.

Environ Health Perspect 2021 May 10;129(5):57005. Epub 2021 May 10.

Department of Molecular Biosciences, University of California Davis (UC Davis) School of Veterinary Medicine, Davis, California, USA.

Background: Epidemiological data link traffic-related air pollution (TRAP) to increased risk of Alzheimer's disease (AD). Preclinical data corroborating this association are largely from studies of male animals exposed acutely or subchronically to high levels of isolated fractions of TRAP. What remains unclear is whether chronic exposure to ambient TRAP modifies AD risk and the influence of sex on this interaction.

Objectives: This study sought to assess effects of chronic exposure to ambient TRAP on the time to onset and severity of AD phenotypes in a preclinical model and to determine whether sex or genetic susceptibility influences outcomes.

Methods: Male and female TgF344-AD rats that express human AD risk genes and wildtype littermates were housed in a vivarium adjacent to a heavily trafficked tunnel in Northern California and exposed for up to 14 months to filtered air (FA) or TRAP drawn from the tunnel and delivered to animals unchanged in real time. Refractive particles in the brain and AD phenotypes were quantified in 3-, 6-, 10-, and 15-month-old animals using hyperspectral imaging, behavioral testing, and neuropathologic measures.

Results: Particulate matter (PM) concentrations in TRAP exposure chambers fluctuated with traffic flow but remained below 24-h PM with aerodynamic diameter less than or equal to 2.5 micrometers () U.S. National Ambient Air Quality Standards limits. Ultrafine PM was a predominant component of TRAP. Nano-sized refractive particles were detected in the hippocampus of TRAP animals. TRAP-exposed animals had more amyloid plaque deposition, higher hyperphosphorylated tau levels, more neuronal cell loss, and greater cognitive deficits in an age-, genotype-, and sex-dependent manner. TRAP-exposed animals also had more microglial cell activation, but not astrogliosis.

Discussion: These data demonstrate that chronic exposure to ambient TRAP promoted AD phenotypes in wildtype and genetically susceptible rats. TRAP effects varied according to age, sex, and genotype, suggesting that AD progression depends on complex interactions between environment and genetics. These findings suggest current regulations are insufficient to protect the aging brain. https://doi.org/10.1289/EHP8905.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1289/EHP8905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110309PMC
May 2021

Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice.

Genome Med 2021 04 26;13(1):69. Epub 2021 Apr 26.

Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.

Background: Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the Na1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified.

Methods: To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior.

Results: Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and Na1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits.

Conclusions: This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A. We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00884-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080386PMC
April 2021

Functional rescue in an Angelman syndrome model following treatment with lentivector transduced hematopoietic stem cells.

Hum Mol Genet 2021 Jun;30(12):1067-1083

Stem Cell Program, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, CA 95817, USA.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by impaired communication skills, ataxia, motor and balance deficits, intellectual disabilities, and seizures. The genetic cause of AS is the neuronal loss of UBE3A expression in the brain. A novel approach, described here, is a stem cell gene therapy which uses lentivector-transduced hematopoietic stem and progenitor cells to deliver functional UBE3A to affected cells. We have demonstrated both the prevention and reversal of AS phenotypes upon transplantation and engraftment of human CD34+ cells transduced with a Ube3a lentivector in a novel immunodeficient Ube3amat-/pat+ IL2rg-/y mouse model of AS. A significant improvement in motor and cognitive behavioral assays as well as normalized delta power measured by electroencephalogram was observed in neonates and adults transplanted with the gene modified cells. Human hematopoietic profiles observed in the lymphoid organs by detection of human immune cells were normal. Expression of UBE3A was detected in the brains of the adult treatment group following immunohistochemical staining illustrating engraftment of the gene-modified cells expressing UBE3A in the brain. As demonstrated with our data, this stem cell gene therapy approach offers a promising treatment strategy for AS, not requiring a critical treatment window.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188406PMC
June 2021

Early Developmental EEG and Seizure Phenotypes in a Full Gene Deletion of Ubiquitin Protein Ligase E3A Rat Model of Angelman Syndrome.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Mar 24.

Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030

Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of the gene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect of maternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared with WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures (FSs). Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased δ power as a potential biomarker of AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/ENEURO.0345-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114899PMC
June 2021

Translational outcomes relevant to neurodevelopmental disorders following early life exposure of rats to chlorpyrifos.

J Neurodev Disord 2020 12 16;12(1):40. Epub 2020 Dec 16.

MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.

Background: Neurodevelopmental disorders (NDDs), including intellectual disability, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), are pervasive, lifelong disorders for which pharmacological interventions are not readily available. Substantial increases in the prevalence of NDDs over a relatively short period may not be attributed solely to genetic factors and/or improved diagnostic criteria. There is now a consensus that multiple genetic loci combined with environmental risk factors during critical periods of neurodevelopment influence NDD susceptibility and symptom severity. Organophosphorus (OP) pesticides have been identified as potential environmental risk factors. Epidemiological studies suggest that children exposed prenatally to the OP pesticide chlorpyrifos (CPF) have significant mental and motor delays and strong positive associations for the development of a clinical diagnosis of intellectual delay or disability, ADHD, or ASD.

Methods: We tested the hypothesis that developmental CPF exposure impairs behavior relevant to NDD phenotypes (i.e., deficits in social communication and repetitive, restricted behavior). Male and female rat pups were exposed to CPF at 0.1, 0.3, or 1.0 mg/kg (s.c.) from postnatal days 1-4.

Results: These CPF doses did not significantly inhibit acetylcholinesterase activity in the blood or brain but significantly impaired pup ultrasonic vocalizations (USV) in both sexes. Social communication in juveniles via positive affiliative 50-kHz USV playback was absent in females exposed to CPF at 0.3 mg/kg and 1.0 mg/kg. In contrast, this CPF exposure paradigm had no significant effect on gross locomotor abilities or contextual and cued fear memory. Ex vivo magnetic resonance imaging largely found no differences between the CPF-exposed rats and the corresponding vehicle controls using strict false discovery correction; however, there were interesting trends in females in the 0.3 mg/kg dose group.

Conclusions: This work generated and characterized a rat model of developmental CPF exposure that exhibits adverse behavioral phenotypes resulting from perinatal exposures at levels that did not significantly inhibit acetylcholinesterase activity in the brain or blood. These data suggest that current regulations regarding safe levels of CPF need to be reconsidered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s11689-020-09342-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745485PMC
December 2020

Developmental exposure to near roadway pollution produces behavioral phenotypes relevant to neurodevelopmental disorders in juvenile rats.

Transl Psychiatry 2020 08 17;10(1):289. Epub 2020 Aug 17.

MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA.

Epidemiological studies consistently implicate traffic-related air pollution (TRAP) and/or proximity to heavily trafficked roads as risk factors for developmental delays and neurodevelopmental disorders (NDDs); however, there are limited preclinical data demonstrating a causal relationship. To test the effects of TRAP, pregnant rat dams were transported to a vivarium adjacent to a major freeway tunnel system in northern California where they were exposed to TRAP drawn directly from the face of the tunnel or filtered air (FA). Offspring remained housed under the exposure condition into which they were born and were tested in a variety of behavioral assays between postnatal day 4 and 50. To assess the effects of near roadway exposure, offspring of dams housed in a standard research vivarium were tested at the laboratory. An additional group of dams was transported halfway to the facility and then back to the laboratory to control for the effect of potential transport stress. Near roadway exposure delayed growth and development of psychomotor reflexes and elicited abnormal activity in open field locomotion. Near roadway exposure also reduced isolation-induced 40-kHz pup ultrasonic vocalizations, with the TRAP group having the lowest number of call emissions. TRAP affected some components of social communication, evidenced by reduced neonatal pup ultrasonic calling and altered juvenile reciprocal social interactions. These findings confirm that living in close proximity to highly trafficked roadways during early life alters neurodevelopment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-00978-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431542PMC
August 2020

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Nat Neurosci 2020 09 13;23(9):1102-1110. Epub 2020 Jul 13.

Departments of Otolaryngology-Head and Neck Surgery, Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41593-020-0665-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483861PMC
September 2020

Effects of early life exposure to traffic-related air pollution on brain development in juvenile Sprague-Dawley rats.

Transl Psychiatry 2020 05 27;10(1):166. Epub 2020 May 27.

Molecular Biosciences, UC Davis School of Veterinary Medicine, Davis, CA, USA.

Epidemiological studies link traffic-related air pollution (TRAP) to increased risk for various neurodevelopmental disorders (NDDs); however, there are limited preclinical data demonstrating a causal relationship between TRAP and adverse neurodevelopmental outcomes. Moreover, much of the preclinical literature reports effects of concentrated ambient particles or diesel exhaust that do not recapitulate the complexity of real-world TRAP exposures. To assess the developmental neurotoxicity of more realistic TRAP exposures, we exposed male and female rats during gestation and early postnatal development to TRAP drawn directly from a traffic tunnel in Northern California and delivered to animals in real-time. We compared NDD-relevant neuropathological outcomes at postnatal days 51-55 in TRAP-exposed animals versus control subjects exposed to filtered air. As indicated by immunohistochemical analyses, TRAP significantly increased microglial infiltration in the CA1 hippocampus, but decreased astrogliosis in the dentate gyrus. TRAP exposure had no persistent effect on pro-inflammatory cytokine levels in the male or female brain, but did significantly elevate the anti-inflammatory cytokine IL-10 in females. In male rats, TRAP significantly increased hippocampal neurogenesis, while in females, TRAP increased granule cell layer width. TRAP had no effect on apoptosis in either sex. Magnetic resonance imaging revealed that TRAP-exposed females, but not males, also exhibited decreased lateral ventricular volume, which was correlated with increased granule cell layer width in the hippocampus in females. Collectively, these data indicate that exposure to real-world levels of TRAP during gestation and early postnatal development modulate neurodevelopment, corroborating epidemiological evidence of an association between TRAP exposure and increased risk of NDDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-020-0845-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264203PMC
May 2020

Cyclin D2-knock-out mice with attenuated dentate gyrus neurogenesis have robust deficits in long-term memory formation.

Sci Rep 2020 05 18;10(1):8204. Epub 2020 May 18.

Department of Neurological Surgery, UC Davis Medical Center, Sacramento, CA, 95817, US.

Neurobehavioral studies have produced contradictory findings concerning the function of neurogenesis in the adult dentate gyrus. Previous studies have proved inconsistent across several behavioral endpoints thought to be dependent on dentate neurogenesis, including memory acquisition, short-term and long-term retention of memory, pattern separation, and reversal learning. We hypothesized that the main function of dentate neurogenesis is long-term memory formation because we assumed that a newly formed and integrated neuron would have a long-term impact on the local neural network. We used a cyclin D2-knock-out (cyclin D2) mouse model of endogenously deficient dentate neurogenesis to test this hypothesis. We found that cyclin D2 mice had robust and sustained loss of long-term memory in two separate behavioral tasks, Morris water maze (MWM) and touchscreen intermediate pattern separation. Moreover, after adjusting for differences in brain volumes determined by magnetic resonance (MR) imaging, reduced dentate neurogenesis moderately correlated with deficits in memory retention after 24 hours. Importantly, cyclin D2 mice did not show deficits in learning acquisition in a touchscreen paradigm of intermediate pattern separation or MWM platform location, indicating intact short-term memory. Further evaluation of cyclin D2 mice is necessary to confirm that deficits are specifically linked to dentate gyrus neurogenesis since cyclin D2 mice also have a reduced size of the olfactory bulb, hippocampus, cerebellum and cortex besides reduced dentate gyrus neurogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-65090-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235216PMC
May 2020

Generation of a Novel Rat Model of Angelman Syndrome with a Complete Ube3a Gene Deletion.

Autism Res 2020 03 21;13(3):397-409. Epub 2020 Jan 21.

Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida.

Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, lack of speech, and ataxia. The gene responsible for AS was identified as Ube3a and it encodes for E6AP, an E3 ubiquitin ligase. Currently, there is very little known about E6AP's mechanism of action in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. Elucidating the mechanistic action of E6AP would enhance our understanding of AS and drive current research into new avenues that could lead to novel therapeutic approaches that target E6AP's various functions. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat phenotypically mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS. Autism Res 2020, 13: 397-409. © 2020 International Society for Autism Research,Wiley Periodicals, Inc. LAY SUMMARY: Angelman syndrome (AS) is a rare genetic disorder characterized by severe intellectual disability, seizures, difficulty speaking, and ataxia. The gene responsible for AS was identified as UBE3A, yet very little is known about its function in vivo or how the lack of this protein in neurons may contribute to the AS phenotype. To facilitate the study of AS, we have generated a novel rat model in which we deleted the rat Ube3a gene using CRISPR. The AS rat mirrors human AS with loss of Ube3a expression in the brain and deficits in motor coordination as well as learning and memory. This model offers a new avenue for the study of AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/aur.2267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787396PMC
March 2020

Imprinting effects of UBE3A loss on synaptic gene networks and Wnt signaling pathways.

Hum Mol Genet 2019 11;28(22):3842-3852

Medical Immunology and Microbiology, University of California (UC) Davis School of Medicine, Davis, CA 95616, USA.

Ubiquitin E3 ligase 3A (UBE3A) encodes an E3 ubiquitin ligase whose loss from the maternal allele causes the neurodevelopmental disorder Angelman syndrome (AS). Previous studies of UBE3A function have not examined full Ube3a deletion in mouse, the complexity of imprinted gene networks in brain nor the molecular basis of systems-level cognitive dysfunctions in AS. We therefore utilized a systems biology approach to elucidate how UBE3A loss impacts the early postnatal brain in a novel CRISPR/Cas9-engineered rat Angelman model of a complete Ube3a deletion. Strand-specific transcriptome analysis of offspring from maternally or paternally inherited Ube3a deletions revealed the expected parental expression patterns of Ube3a sense and antisense transcripts by postnatal day 2 (P2) in hypothalamus and day 9 (P9) in cortex, compared to wild-type littermates. The dependency of genome-wide effects on parent-of-origin, Ube3a genotype and time (P2 and P9) was investigated through transcriptome (RNA sequencing of cortex and hypothalamus) and methylome (whole-genome bisulfite sequencing of hypothalamus). Weighted gene co-expression and co-methylation network analyses identified co-regulated networks in maternally inherited Ube3a deletion offspring enriched in postnatal developmental processes including Wnt signaling, synaptic regulation, neuronal and glial functions, epigenetic regulation, ubiquitin, circadian entrainment and splicing. Furthermore, we showed that loss of the paternal Ube3a antisense transcript resulted in both unique and overlapping dysregulated gene pathways with maternal loss, predominantly at the level of differential methylation. Together, these results provide a holistic examination of the molecular impacts of UBE3A loss in brain, supporting the existence of interactive epigenetic networks between maternal and paternal transcripts at the Ube3a locus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddz221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275372PMC
November 2019

Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size.

Brain 2019 09;142(9):2617-2630

GeneDx, Clinical Genomics, 207 Perry Parkway Gaithersburg, MD, USA.

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awz198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736092PMC
September 2019

Persistent behavior deficits, neuroinflammation, and oxidative stress in a rat model of acute organophosphate intoxication.

Neurobiol Dis 2020 01 21;133:104431. Epub 2019 Mar 21.

Department of Molecular Biosciences, School of Veterinary Medicine, University of California-Davis, 1089 Veterinary Medicine Drive, Davis, CA 95616, USA; MIND Institute, School of Medicine, University of California-Davis, 2825 50th Street, Sacramento, CA 95817, USA. Electronic address:

Current medical countermeasures for organophosphate (OP)-induced status epilepticus (SE) are not effective in preventing long-term morbidity and there is an urgent need for improved therapies. Rat models of acute intoxication with the OP, diisopropylfluorophosphate (DFP), are increasingly being used to evaluate therapeutic candidates for efficacy in mitigating the long-term neurologic effects associated with OP-induced SE. Many of these therapeutic candidates target neuroinflammation and oxidative stress because of their implication in the pathogenesis of persistent neurologic deficits associated with OP-induced SE. Critical to these efforts is the rigorous characterization of the rat DFP model with respect to outcomes associated with acute OP intoxication in humans, which include long-term electroencephalographic, neurobehavioral, and neuropathologic effects, and their temporal relationship to neuroinflammation and oxidative stress. To address these needs, we examined a range of outcomes at later times post-exposure than have previously been reported for this model. Adult male Sprague-Dawley rats were given pyridostigmine bromide (0.1 mg/kg, im) 30 min prior to administration of DFP (4 mg/kg, sc), which was immediately followed by atropine sulfate (2 mg/kg, im) and pralidoxime (25 mg/kg, im). This exposure paradigm triggered robust electroencephalographic and behavioral seizures that rapidly progressed to SE lasting several hours in 90% of exposed animals. Animals that survived DFP-induced SE (~70%) exhibited spontaneous recurrent seizures and hyperreactive responses to tactile stimuli over the first 2 months post-exposure. Performance in the elevated plus maze, open field, and Pavlovian fear conditioning tests indicated that acute DFP intoxication reduced anxiety-like behavior and impaired learning and memory at 1 and 2 months post-exposure in the absence of effects on general locomotor behavior. Immunohistochemical analyses revealed significantly increased expression of biomarkers of reactive astrogliosis, microglial activation and oxidative stress in multiple brain regions at 1 and 2 months post-DFP, although there was significant spatiotemporal heterogeneity across these endpoints. Collectively, these data largely support the relevance of the rat model of acute DFP intoxication as a model for acute OP intoxication in the human, and support the hypothesis that neuroinflammation and/or oxidative stress represent potential therapeutic targets for mitigating the long-term neurologic sequelae of acute OP intoxication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2019.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754818PMC
January 2020

Genetic mutations in Ca signaling alter dendrite morphology and social approach in juvenile mice.

Genes Brain Behav 2019 01 6;18(1):e12526. Epub 2018 Nov 6.

Department of Molecular Biosciences, University of California-Davis, School of Veterinary Medicine, Davis, California.

Dendritic morphology is a critical determinant of neuronal connectivity, and calcium signaling plays a predominant role in shaping dendrites. Altered dendritic morphology and genetic mutations in calcium signaling are both associated with neurodevelopmental disorders (NDDs). In this study we tested the hypothesis that dendritic arborization and NDD-relevant behavioral phenotypes are altered by human mutations that modulate calcium-dependent signaling pathways implicated in NDDs. The dendritic morphology of pyramidal neurons in CA1 hippocampus and somatosensory cortex was quantified in Golgi-stained brain sections from juvenile mice of both sexes expressing either a human gain-of-function mutation in ryanodine receptor 1 (T4826I-RYR1), a human CGG repeat expansion (170-200 CGG repeats) in the fragile X mental retardation gene 1 (FMR1 premutation), both mutations (double mutation; DM), or wildtype mice. In hippocampal neurons, increased dendritic arborization was observed in male T4826I-RYR1 and, to a lesser extent, male FMR1 premutation neurons. Dendritic morphology of cortical neurons was altered in both sexes of FMR1 premutation and DM animals with the most pronounced differences seen in DM females. Genotype also impaired behavior, as assessed using the three-chambered social approach test. The most striking lack of sociability was observed in DM male and female mice. In conclusion, mutations that alter the fidelity of calcium signaling enhance dendritic arborization in a brain region- and sex-specific manner and impair social behavior in juvenile mice. The phenotypic outcomes of these mutations likely provide a susceptible biological substrate for additional environmental stressors that converge on calcium signaling to determine individual NDD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/gbb.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540090PMC
January 2019

Autism-specific maternal autoantibodies produce behavioral abnormalities in an endogenous antigen-driven mouse model of autism.

Mol Psychiatry 2020 11 28;25(11):2994-3009. Epub 2018 Jun 28.

Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, CA, USA.

Immune dysregulation has been noted consistently in individuals with autism spectrum disorder (ASD) and their families, including the presence of autoantibodies reactive to fetal brain proteins in nearly a quarter of mothers of children with ASD versus <1% in mothers of typically developing children. Our lab recently identified the peptide epitope sequences on seven antigenic proteins targeted by these maternal autoantibodies. Through immunization with these peptide epitopes, we have successfully created an endogenous, antigen-driven mouse model that ensures a constant exposure to the salient autoantibodies throughout gestation in C57BL/6J mice. This exposure more naturally mimics what is observed in mothers of children with ASD. Male and female offspring were tested using a comprehensive sequence of behavioral assays, as well as measures of health and development highly relevant to ASD. We found that MAR-ASD male and female offspring had significant alterations in development and social interactions during dyadic play. Although 3-chambered social approach was not significantly different, fewer social interactions with an estrous female were noted in the adult male MAR-ASD animals, as well as reduced vocalizations emitted in response to social cues with robust repetitive self-grooming behaviors relative to saline treated controls. The generation of MAR-ASD-specific epitope autoantibodies in female mice prior to breeding created a model that demonstrates for the first time that ASD-specific antigen-induced maternal autoantibodies produced alterations in a constellation of ASD-relevant behaviors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-018-0126-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310680PMC
November 2020

Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome.

Neurobiol Learn Mem 2019 11 23;165:106874. Epub 2018 May 23.

MIND Institute, University of California, Davis School of Medicine, Department of Psychiatry and Behavioral Sciences, Sacramento, CA, USA. Electronic address:

Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans. The majority of previous research using PWS preclinical models focused on characterization of the hyperphagic and metabolic phenotypes. However, a crucial understudied clinical phenotype is cognitive impairments and thus we investigated the learning and memory abilities using a model of PWS, with a heterozygous deletion in Snord116. We utilized the novel object recognition task, which doesn't require external motivation, or exhaustive swim training. Automated findings were further confirmed with manual scoring by a highly trained blinded investigator. We discovered deficits in Snord116+/- mutant mice in the novel object recognition, location memory and tone cue fear conditioning assays when compared to age-, sex- matched, littermate control Snord116+/+ mice. Further, we confirmed that despite physical neo-natal developmental delays, Snord116+/- mice had normal exploratory and motor abilities. These results show that the Snord116+/- deletion murine model is a valuable preclinical model for investigating learning and memory impairments in individuals with PWS without common confounding phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nlm.2018.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520209PMC
November 2019

Autistic traits in epilepsy models: Why, when and how?

Epilepsy Res 2018 08 18;144:62-70. Epub 2018 May 18.

INMED, Aix-Marseille University, INSERM, Marseille, France.

Autism spectrum disorder (ASD) is a common comorbidity of epilepsy and seizures and/or epileptiform activity are observed in a significant proportion of ASD patients. Current research also implies that autistic traits can be observed to a various degree in mice and rats with seizures. This suggests that there are shared mechanisms in both ASD and epilepsy syndromes. Here, we first review the standard, validated methods used to assess autistic traits in animal models as well as their limitations with regards to epilepsy models. We then discuss two of the potential pathological processes that could be shared between ASD and epilepsy. We first focus on functional implications of neuroinflammation including changes to excitable networks mediated by inflammatory regulators. Finally we examine mechanisms at the cellular and network level involved in neuronal excitability, timing and network coordination that may directly lead to behavioral disturbances present in both epilepsy and ASD. This mini-review summarizes the work first presented at an Investigators Workshop at the 2016 American Epilepsy Society meeting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eplepsyres.2018.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978734PMC
August 2018

Behavioral and neuroanatomical approaches in models of neurodevelopmental disorders: opportunities for translation.

Curr Opin Neurol 2018 04;31(2):126-133

Mouse Imaging Centre, The Hospital for Sick Children, Toronto, Canada.

Purpose Of Review: This review highlights the invaluable contribution of in-vivo rodent models in dissecting the underlying neurobiology for numerous neurodevelopmental disorders. Currently, models are routinely generated with precision genomics and characterized for research on neurodevelopmental disorders. In order to impact translation, outcome measures that are translationally relevant are essential. This review emphasizes the importance of accurate neurobehavioral and anatomical analyses.

Recent Findings: Numerous well validated assays for testing alterations across behavioral domains with sensitivity and throughput have become important tools for studying the effects of genetic mutations on neurodevelopment. Recent work has highlighted relationships and links between behavioral outcomes and various anatomical metrics from neuroimaging via magnetic resonance. These readouts are biological markers and outcome measures for translational research and will be have important roles for genetic or pharmacologic intervention strategies.

Summary: Combinatorial approaches that leverage translationally relevant behavior and neuroanatomy can be used to develop a platform for assessment of cutting edge preclinical models. Reliable, robust behavioral phenotypes in preclinical model systems, with clustering of brain disease will lead to well informed, precise biochemical mechanistic hypotheses. Ultimately, these steadfast workhorse techniques will accelerate the progress of developing and testing targeted treatments for multiple neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/WCO.0000000000000537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846342PMC
April 2018

Sex Differences in the Effects of a Kappa Opioid Receptor Antagonist in the Forced Swim Test.

Front Pharmacol 2018 14;9:93. Epub 2018 Feb 14.

Neuroscience Graduate Group, University of California, Davis, Davis, CA, United States.

There is growing evidence that kappa opioid receptor (KOR) antagonists could be a useful class of therapeutics for treating depression and anxiety. However, the overwhelming majority of preclinical investigations examining the behavioral effects of KOR antagonists have been in male rodents. Here, we examined the effects of the long-acting KOR antagonist nor-binaltophimine (norBNI) on immobility in the forced swim test in males and females of two different rodent species (C57Bl/6J and California mice). Consistent with previous reports, norBNI (10 mg/kg) decreased immobility in the forced swim test for male C57Bl/6J and California mice. Surprisingly, dose-response studies in female C57Bl/6J and California mice showed that norBNI did not reduce immobility. Pharmacokinetic analyses showed that metabolism and brain concentrations of norBNI were similar in male and female C57Bl/6J. In the nucleus accumbens of male but not female C57Bl/6J, norBNI increased phosphorylation of c-Jun N-terminal kinase (pJNK), a putative mechanism for norBNI action. However, no differences in pJNK were observed in male or female California mice. Together, these results suggest that immobility in the forced swim test is less dependent on endogenous KOR signaling in female rodents and highlight the importance of examining the effects of possible therapeutic agents in both males and females.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817081PMC
February 2018

SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function.

Cell Rep 2018 02;22(9):2246-2253

Department of Pharmacology, UC Davis School of Medicine, Davis, CA 95616, USA. Electronic address:

Altering AMPA receptor (AMPAR) content at synapses is a key mechanism underlying the regulation of synaptic strength during learning and memory. Previous work demonstrated that SynDIG1 (synapse differentiation-induced gene 1) encodes a transmembrane AMPAR-associated protein that regulates excitatory synapse strength and number. Here we show that the related protein SynDIG4 (also known as Prrt1) modifies AMPAR gating properties in a subunit-dependent manner. Young SynDIG4 knockout (KO) mice have weaker excitatory synapses, as evaluated by immunocytochemistry and electrophysiology. Adult SynDIG4 KO mice show complete loss of tetanus-induced long-term potentiation (LTP), while mEPSC amplitude is reduced by only 25%. Furthermore, SynDIG4 KO mice exhibit deficits in two independent cognitive assays. Given that SynDIG4 colocalizes with the AMPAR subunit GluA1 at non-synaptic sites, we propose that SynDIG4 maintains a pool of extrasynaptic AMPARs necessary for synapse development and function underlying higher-order cognitive plasticity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856126PMC
February 2018

Developmental social communication deficits in the Shank3 rat model of phelan-mcdermid syndrome and autism spectrum disorder.

Autism Res 2018 04 29;11(4):587-601. Epub 2018 Jan 29.

University of California, Davis, MIND Institute, School of Medicine, Sacramento, CA.

Mutations in the SHANK3 gene have been discovered in autism spectrum disorder (ASD), and the intellectual disability, Phelan-McDermid Syndrome. This study leveraged a new rat model of Shank3 deficiency to assess complex behavioral phenomena, unique to rats, which display a richer social behavior repertoire than mice. Uniquely detectable emissions of ultrasonic vocalizations (USV) in rats serve as situation-dependent affective signals and accomplish important communicative functions. We report, for the first time, a call and response acoustic playback assay of bidirectional social communication in juvenile Shank3 rats. Interestingly, we found that Shank3-deficient null males did not demonstrate the enhanced social approach behavior typically exhibited following playback of pro-social USV. Concomitantly, we discovered that emission of USV in response to playback was not genotype-dependent and emitted response calls were divergent in meaning. This is the first report of these socially relevant responses using a genetic model of ASD. A comprehensive and empirical analysis of vigorous play during juvenile reciprocal social interactions further revealed fewer bouts and reduced durations of time spent playing by multiple key parameters, including reduced anogenital sniffing and allogrooming. We further discovered that male null Shank3-deficient pups emitted fewer isolation-induced USV than Shank3 wildtype controls. Postnatal whole brain anatomical phenotyping was applied to visualize anatomical substrates that underlie developmental phenotypes. The data presented here lend support for the important role of Shank3 in social communication, the core symptom domain of ASD. By increasing the number of in vivo functional outcome measures, we improved the likelihood for identifying and moving forward with medical interventions. Autism Res 2018, 11: 587-601. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary: Clinically relevant outcomes are required to demonstrate the utility of therapeutics. We introduce findings in a rat model, and assess the impact of mutations in Shank3, an autism risk gene. We found that males with deficient expression of Shank3 did not demonstrate typical responses in a bi-directional social communication test and that social interaction was lower on key parameters. Outcome measures reported herein extend earlier results in mice and capture responses to acoustic calls, which is analogous to measuring receptive and expressive communication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/aur.1925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903935PMC
April 2018

mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex.

Neuropsychopharmacology 2018 05 5;43(6):1457-1465. Epub 2017 Dec 5.

Department of Neurology, Boston Children's Hospital, F.M. Kirby Neurobiology Center, Harvard Medical School, Boston, MA, USA.

Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy. This model uniquely enables the in vivo characterization and rescue of the electrographic seizures associated with TSC. We demonstrate that inhibition of mGluR5 corrects hyperactivity, seizures, and elevated de novo synaptic protein synthesis. Conversely, positive allosteric modulation of mGluR5 results in the exacerbation of hyperactivity and epileptic phenotypes. The data suggest a meaningful therapeutic potential for mGluR5 NAMs in TSC, which warrants clinical exploration and the continued development of mGluR5 therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2017.295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916364PMC
May 2018

Neuronal overexpression of Ube3a isoform 2 causes behavioral impairments and neuroanatomical pathology relevant to 15q11.2-q13.3 duplication syndrome.

Hum Mol Genet 2017 10;26(20):3995-4010

Texas A&M, College Station, TX, USA.

Maternally derived copy number gains of human chromosome 15q11.2-q13.3 (Dup15q syndrome or Dup15q) cause intellectual disability, epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. Dup15q syndrome is one of the most common and penetrant chromosomal abnormalities observed in individuals with autism spectrum disorder (ASD). Although ∼40 genes are located in the 15q11.2-q13.3 region, overexpression of the ubiquitin-protein E3A ligase (UBE3A) gene is thought to be the predominant molecular cause of the phenotypes observed in Dup15q syndrome. The UBE3A gene demonstrates maternal-specific expression in neurons and loss of maternal UBE3A causes Angelman syndrome, a neurodevelopmental disorder with some overlapping neurological features to Dup15q. To directly test the hypothesis that overexpression of UBE3A is an important underlying molecular cause of neurodevelopmental dysfunction, we developed and characterized a mouse overexpressing Ube3a isoform 2 in excitatory neurons. Ube3a isoform 2 is conserved between mouse and human and known to play key roles in neuronal function. Transgenic mice overexpressing Ube3a isoform 2 in excitatory forebrain neurons exhibited increased anxiety-like behaviors, learning impairments, and reduced seizure thresholds. However, these transgenic mice displayed normal social approach, social interactions, and repetitive motor stereotypies that are relevant to ASD. Reduced forebrain, hippocampus, striatum, amygdala, and cortical volume were also observed. Altogether, these findings show neuronal overexpression of Ube3a isoform 2 causes phenotypes translatable to neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddx289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886211PMC
October 2017

Germline Chd8 haploinsufficiency alters brain development in mouse.

Nat Neurosci 2017 Aug 26;20(8):1062-1073. Epub 2017 Jun 26.

Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, California, USA.

The chromatin remodeling gene CHD8 represents a central node in neurodevelopmental gene networks implicated in autism. We examined the impact of germline heterozygous frameshift Chd8 mutation on neurodevelopment in mice. Chd8 mice displayed normal social interactions with no repetitive behaviors but exhibited cognitive impairment correlated with increased regional brain volume, validating that phenotypes of Chd8 mice overlap pathology reported in humans with CHD8 mutations. We applied network analysis to characterize neurodevelopmental gene expression, revealing widespread transcriptional changes in Chd8 mice across pathways disrupted in neurodevelopmental disorders, including neurogenesis, synaptic processes and neuroimmune signaling. We identified a co-expression module with peak expression in early brain development featuring dysregulation of RNA processing, chromatin remodeling and cell-cycle genes enriched for promoter binding by Chd8, and we validated increased neuronal proliferation and developmental splicing perturbation in Chd8 mice. This integrative analysis offers an initial picture of the consequences of Chd8 haploinsufficiency for brain development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nn.4592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008102PMC
August 2017
-->