Publications by authors named "Benjamin A Samuels"

14 Publications

  • Page 1 of 1

Engrailed 2 deficiency and chronic stress alter avoidance and motivation behaviors.

Behav Brain Res 2021 Sep 13;413:113466. Epub 2021 Jul 13.

Behavioral and Systems Neuroscience Area, Department of Psychology, Rutgers University-New Brunswick, Piscataway, NJ, 08854, USA. Electronic address:

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impairments in social interaction, cognition, and communication, as well as the presence of repetitive or stereotyped behaviors and interests. ASD is most often studied as a neurodevelopmental disease, but it is a lifelong disorder. Adults with ASD experience more stressful life events and greater perceived stress, and frequently have comorbid mood disorders such as anxiety and depression. It remains unclear whether adult exposure to chronic stress can exacerbate the behavioral and neurodevelopmental phenotypes associated with ASD. To address this issue, we first investigated whether adult male and female Engrailed-2 deficient (En2-KO, En2-/-) mice, which display behavioral disturbances in avoidance tasks and dysregulated monoaminergic neurotransmitter levels, also display impairments in instrumental behaviors associated with motivation, such as the progressive ratio task. We then exposed adult En2-KO mice to chronic environmental stress (CSDS, chronic social defeat stress), to determine if stress exacerbated the behavioral and neuroanatomical effects of En2 deletion. En2-/- mice showed impaired instrumental acquisition and significantly lower breakpoints in a progressive ratio test, demonstrating En2 deficiency decreases motivation to exert effort for reward. Furthermore, adult CSDS exposure increased avoidance behaviors in En2-KO mice. Interestingly, adult CSDS exposure also exacerbated the deleterious effects of En2 deficiency on forebrain-projecting monoaminergic fibers. Our findings thus suggest that adult exposure to stress may exacerbate behavioral and neuroanatomical phenotypes associated with developmental effects of genetic En2 deficiency.
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http://dx.doi.org/10.1016/j.bbr.2021.113466DOI Listing
September 2021

Activation of Basolateral Amygdala to Nucleus Accumbens Projection Neurons Attenuates Chronic Corticosterone-Induced Behavioral Deficits in Male Mice.

Front Behav Neurosci 2021 24;15:643272. Epub 2021 Feb 24.

Neuroscience Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, United States.

The basolateral amygdala (BLA) is critical for reward behaviors a projection to the nucleus accumbens (NAc). Specifically, BLA-NAc projections are involved in reinforcement learning, reward-seeking, sustained instrumental responding, and risk behaviors. However, it remains unclear whether chronic stress interacts with BLA-NAc projection neurons to result in maladaptive behaviors. Here we take a chemogenetic, projection-specific approach to clarify how NAc-projecting BLA neurons affect avoidance, reward, and feeding behaviors in male mice. Then, we examine whether chemogenetic activation of NAc-projecting BLA neurons attenuates the maladaptive effects of chronic corticosterone (CORT) administration on these behaviors. CORT mimics the behavioral and neural effects of chronic stress exposure. We found a nuanced role of BLA-NAc neurons in mediating reward behaviors. Surprisingly, activation of BLA-NAc projections rescues CORT-induced deficits in the novelty suppressed feeding, a behavior typically associated with avoidance. Activation of BLA-NAc neurons also increases instrumental reward-seeking without affecting free-feeding in chronic CORT mice. Taken together, these data suggest that NAc-projecting BLA neurons are involved in chronic CORT-induced maladaptive reward and motivation behaviors.
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http://dx.doi.org/10.3389/fnbeh.2021.643272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943928PMC
February 2021

Behavioral response to fluoxetine in both female and male mice is modulated by dentate gyrus granule cell activity.

Neurobiol Stress 2020 Nov 17;13:100257. Epub 2020 Oct 17.

Behavioral & Systems Neuroscience, Department of Psychology, USA.

Depression is a complex psychiatric disorder that is a major burden on society, with only ~33% of depressed patients attaining remission upon initial monotherapy with a selective serotonin reuptake inhibitor (SSRI). In preclinical studies using rodents, chronic stress paradigms, such as chronic corticosterone and social instability stress, are used to induce avoidance behaviors associated with negative affective states. Chronic fluoxetine (FLX; an SSRI) treatment reverses these chronic stress-induced behavioral changes in some, but not all mice, permitting stratification of mice into behavioral responders and non-responders to FLX. We previously reported that 5-HT receptors, which are Gi-coupled inhibitory receptors, on mature granule cells (GCs) in the dentate gyrus (DG) are necessary and sufficient for the behavioral, neurogenic, and neuroendocrine response to chronic SSRI treatment. Since inhibition of mature DG GCs through cell autonomous Gi-coupled receptors is critical for mounting an antidepressant response, we assessed the relationship between behavioral response to FLX and DG GC activation in FLX responders, non-responders, and stress controls in both male and female mice. Intriguingly, using disparate stress paradigms, we found that male and female behavioral FLX responders show decreased DG GC activation (as measured by cFos immunostaining) relative to non-responders and stress controls. We then show in both sexes that chronic inhibition of ventral DG GCs (through usage of Gi-DREADDs) results in a decrease in maladaptive avoidance behaviors, while ventral DG GCs stimulation with Gq-DREADDs increases maladaptive behaviors. Finally, we were able to bidirectionally control the behavioral response to FLX through modulation of DG GCs. Chronic inhibition of ventral DG GCs with Gi-DREADDs converted FLX non-responders into responders, while activation of ventral DG GCs with Gq-DREADDs converted FLX responders into non-responders. This study illustrates ventral DG GC activity is a major modulator of the behavioral response to FLX in both male and female mice.
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http://dx.doi.org/10.1016/j.ynstr.2020.100257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739193PMC
November 2020

Early-life stress alters affective behaviors in adult mice through persistent activation of CRH-BDNF signaling in the oval bed nucleus of the stria terminalis.

Transl Psychiatry 2020 11 11;10(1):396. Epub 2020 Nov 11.

Department of Psychology, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.

Early-life stress (ELS) leads to stress-related psychopathology in adulthood. Although dysfunction of corticotropin-releasing hormone (CRH) signaling in the bed nucleus of the stria terminalis (BNST) mediates chronic stress-induced maladaptive affective behaviors that are historically associated with mood disorders such as anxiety and depression, it remains unknown whether ELS affects CRH function in the adult BNST. Here we applied a well-established ELS paradigm (24 h maternal separation (MS) at postnatal day 3) and assessed the effects on CRH signaling and electrophysiology in the oval nucleus of BNST (ovBNST) of adult male mouse offspring. ELS increased maladaptive affective behaviors, and amplified mEPSCs and decreased M-currents (a voltage-gated K current critical for stabilizing membrane potential) in ovBNST CRH neurons, suggesting enhanced cellular excitability. Furthermore, ELS increased the numbers of CRH and PACAP (the pituitary adenylate cyclase-activating polypeptide, an upstream CRH regulator) cells and decreased STEP (striatal-enriched protein tyrosine phosphatase, a CRH inhibitor) cells in BNST. Interestingly, ELS also increased BNST brain-derived neurotrophic factor (BDNF) expression, indicating enhanced neuronal plasticity. These electrophysiological and behavioral effects of ELS were reversed by chronic application of the CRHR1-selective antagonist R121919 into ovBNST, but not when BDNF was co-administered. In addition, the neurophysiological effects of BDNF on M-currents and mEPSCs in BNST CRH neurons mimic effects and were abolished by PKC antagonism. Together, our findings indicate that ELS results in a long-lasting activation of CRH signaling in the mouse ovBNST. These data highlight a regulatory role of CRHR1 in the BNST and for BDNF signaling in mediating ELS-induced long-term behavioral changes.
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http://dx.doi.org/10.1038/s41398-020-01070-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658214PMC
November 2020

Perinatal exposure to bisphenol A at the intersection of stress, anxiety, and depression.

Neurotoxicol Teratol 2020 May - Jun;79:106884. Epub 2020 Apr 11.

Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ. USA.

Endocrine-disrupting compounds (EDCs) are common contaminants in our environment that interfere with typical endocrine function. EDCs can act on steroid and nuclear receptors or alter hormone production. One particular EDC of critical concern is bisphenol A (BPA) due to its potential harm during the perinatal period of development. Previous studies suggest that perinatal exposure to BPA alters several neurotransmitter systems and disrupts behaviors associated with depression and anxiety in the rodent offspring later in life. Thus, dysregulation in neurotransmission may translate to behavioral phenotypes observed in mood and arousal. Many of the systems disrupted by BPA also overlap with the stress system, although little evidence exists on the effects of perinatal BPA exposure in relation to stress and behavior. The purpose of this review is to explore studies involved in perinatal BPA exposure and the stress response at neurochemical and behavioral endpoints. Although more research is needed, we suggest that perinatal BPA exposure is likely inducing variations in behavioral phenotypes that modulate their action through dysregulation of neurotransmitter systems sensitive to stress and endocrine disruption.
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http://dx.doi.org/10.1016/j.ntt.2020.106884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754613PMC
May 2021

Chronic Stress Induces Maladaptive Behaviors by Activating Corticotropin-Releasing Hormone Signaling in the Mouse Oval Bed Nucleus of the Stria Terminalis.

J Neurosci 2020 03 13;40(12):2519-2537. Epub 2020 Feb 13.

Department of Psychology, Rutgers University, Piscataway, New Jersey 08854,

The bed nucleus of the stria terminalis (BNST) is a forebrain region highly responsive to stress that expresses corticotropin-releasing hormone (CRH) and is implicated in mood disorders, such as anxiety. However, the exact mechanism by which chronic stress induces CRH-mediated dysfunction in BNST and maladaptive behaviors remains unclear. Here, we first confirmed that selective acute optogenetic activation of the oval nucleus BNST (ovBNST) increases maladaptive avoidance behaviors in male mice. Next, we found that a 6 week chronic variable mild stress (CVMS) paradigm resulted in maladaptive behaviors and increased cellular excitability of ovBNST CRH neurons by potentiating mEPSC amplitude, altering the resting membrane potential, and diminishing M-currents (a voltage-gated K current that stabilizes membrane potential) in slices. CVMS also increased c-fos cells in ovBNST following handling. We next investigated potential molecular mechanism underlying the electrophysiological effects and observed that CVMS increased CRH and pituitary adenylate cyclase-activating polypeptide (PACAP; a CRH upstream regulator) cells but decreased striatal-enriched protein tyrosine phosphatase (a STEP CRH inhibitor) cells in ovBNST. Interestingly, the electrophysiological effects of CVMS were reversed by CRHR1-selective antagonist R121919 application. CVMS also activated protein kinase A (PKA) in BNST, and chronic infusion of the PKA-selective antagonist H89 into ovBNST reversed the effects of CVMS. Coadministration of the PKA agonist forskolin prevented the beneficial effects of R121919. Finally, CVMS induced an increase in surface expression of phosphorylated GluR1 (S845) in BNST. Collectively, these findings highlight a novel and indispensable stress-induced role for PKA-dependent CRHR1 signaling in activating BNST CRH neurons and mediating maladaptive behaviors. Chronic stress and acute activation of oval bed nucleus of the stria terminalis (ovBNST) induces maladaptive behaviors in rodents. However, the precise molecular and electrophysiological mechanisms underlying these effects remain unclear. Here, we demonstrate that chronic variable mild stress activates corticotropin-releasing hormone (CRH)-associated stress signaling and CRH neurons in ovBNST by potentiating mEPSC amplitude and decreasing M-current in male mice. These electrophysiological alterations and maladaptive behaviors were mediated by BNST protein kinase A-dependent CRHR1 signaling. Our results thus highlight the importance of BNST CRH dysfunction in chronic stress-induced disorders.
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http://dx.doi.org/10.1523/JNEUROSCI.2410-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083537PMC
March 2020

Chronic corticosterone administration induces negative valence and impairs positive valence behaviors in mice.

Transl Psychiatry 2019 12 10;9(1):337. Epub 2019 Dec 10.

Neuroscience Graduate Program, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.

Behavioral approaches utilizing rodents to study mood disorders have focused primarily on negative valence behaviors associated with potential threat (anxiety-related behaviors). However, for disorders such as depression, positive valence behaviors that assess reward processing may be more translationally valid and predictive of antidepressant treatment outcome. Chronic corticosterone (CORT) administration is a well-validated pharmacological stressor that increases avoidance in negative valence behaviors associated with anxiety. However, whether chronic stress paradigms such as CORT administration also lead to deficits in positive valence behaviors remains unclear. We treated male C57BL/6J mice with chronic CORT and assessed both negative and positive valence behaviors. We found that CORT induced avoidance in the open field and NSF. Interestingly, CORT also impaired instrumental acquisition, reduced sensitivity to a devalued outcome, reduced breakpoint in progressive ratio, and impaired performance in probabilistic reversal learning. Taken together, these results demonstrate that chronic CORT administration at the same dosage both induces avoidance in negative valence behaviors associated with anxiety and impairs positive valence behaviors associated with reward processing. These data suggest that CORT administration is a useful experimental system for preclinical approaches to studying stress-induced mood disorders.
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http://dx.doi.org/10.1038/s41398-019-0674-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904464PMC
December 2019

Social instability is an effective chronic stress paradigm for both male and female mice.

Neuropharmacology 2019 12 16;160:107780. Epub 2019 Sep 16.

Behavioral & Systems Neuroscience, Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Rd, Piscataway, NJ, USA. Electronic address:

Despite stress-associated disorders having a higher incidence rate in females, preclinical research mainly focuses on males. Chronic stress paradigms, such as chronic social defeat and chronic corticosterone (CORT) administration, were mainly designed and validated in males and subsequent attempts to use these paradigms in females has demonstrated sex differences in the behavioral and HPA axis response to stress. Here, we assessed the behavioral response to chronic CORT exposure and developed a social stress paradigm, social instability stress (SIS), which exposes adult mice to unstable social hierarchies every 3 days for 7 weeks. Sex differences in response to chronic CORT emerged, with negative valence behaviors induced in CORT treated males, not females. SIS effectively induces negative valence behaviors in the open field, light dark, and novelty suppressed feeding tests, increases immobility in the forced swim test, and activates the hypothalamus-pituitary-adrenal (HPA) axis in both males and females. Importantly, while there were effects of estrous cycle on behavior, this variability did not impact the overall effects of SIS on behavior, suggesting estrous does not need to be tracked while utilizing SIS. Furthermore, the effects of SIS on negative valence behaviors were also reversed following chronic antidepressant treatment with fluoxetine (FLX) in both males and females. SIS also reduced adult hippocampal neurogenesis in female mice, while chronic FLX treatment increased adult hippocampal neurogenesis in both males and females. Overall, these data demonstrate that the SIS paradigm is an ethologically valid approach that effectively induces chronic stress in both adult male and adult female mice.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935299PMC
December 2019

S 38093, a histamine H antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice.

Sci Rep 2017 02 20;7:42946. Epub 2017 Feb 20.

CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer's disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent "context discrimination (CS) test" in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits.
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http://dx.doi.org/10.1038/srep42946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5317168PMC
February 2017

Mechanisms underlying the antidepressant response and treatment resistance.

Front Behav Neurosci 2014 27;8:208. Epub 2014 Jun 27.

Department of Psychiatry, New York State Psychiatric Institute, Columbia University Medical Center, Research Foundation for Mental Hygiene, Inc. New York, NY, USA.

Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment-resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance.
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http://dx.doi.org/10.3389/fnbeh.2014.00208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4073308PMC
July 2014

Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors.

PLoS One 2014 17;9(1):e85136. Epub 2014 Jan 17.

Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Background: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most common form of medication treatment for major depression. However, approximately 50% of depressed patients fail to achieve an effective treatment response. Understanding how gene expression systems respond to treatments may be critical for understanding antidepressant resistance.

Methods: We take a novel approach to this problem by demonstrating that the gene expression system of the dentate gyrus responds to fluoxetine (FLX), a commonly used antidepressant medication, in a stereotyped-manner involving changes in the expression levels of thousands of genes. The aggregate behavior of this large-scale systemic response was quantified with principal components analysis (PCA) yielding a single quantitative measure of the global gene expression system state.

Results: Quantitative measures of system state were highly correlated with variability in levels of antidepressant-sensitive behaviors in a mouse model of depression treated with fluoxetine. Analysis of dorsal and ventral dentate samples in the same mice indicated that system state co-varied across these regions despite their reported functional differences. Aggregate measures of gene expression system state were very robust and remained unchanged when different microarray data processing algorithms were used and even when completely different sets of gene expression levels were used for their calculation.

Conclusions: System state measures provide a robust method to quantify and relate global gene expression system state variability to behavior and treatment. State variability also suggests that the diversity of reported changes in gene expression levels in response to treatments such as fluoxetine may represent different perspectives on unified but noisy global gene expression system state level responses. Studying regulation of gene expression systems at the state level may be useful in guiding new approaches to augmentation of traditional antidepressant treatments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085136PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894967PMC
September 2014

Olfactory deficits cause anxiety-like behaviors in mice.

J Neurosci 2012 May;32(19):6718-25

Department of Neuroscience and the Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.

Anxiety disorders are characterized by persistent fear in the absence of immediate threat and represent the most common psychiatric diseases, with an estimated 28% lifetime prevalence worldwide (Kessler et al., 2010). While symptoms of anxiety are typically evoked by sensory stimuli, it is unknown whether sensory deficits contribute to the development of anxiety disorders. Here we examine the effect of defined genetic mutations that compromise the function of the olfactory system on the development of anxiety-like behaviors in mice. We show that the functional inactivation of the main olfactory epithelium, but not the vomeronasal organ, causes elevated levels of anxiety. Anxiety-like behaviors are also observed in mice with a monoclonal nose, that are able to detect and discriminate odors but in which the patterns of odor-evoked neural activity are perturbed. In these mice, plasma corticosterone levels are elevated, suggesting that olfactory deficits can lead to chronic stress. These results demonstrate a central role for olfactory sensory cues in modulating anxiety in mice.
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http://dx.doi.org/10.1523/JNEUROSCI.4287-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367161PMC
May 2012

Neurogenesis and affective disorders.

Eur J Neurosci 2011 Mar;33(6):1152-9

Department of Psychiatry, Columbia University, New York, NY 10032, USA.

The neurogenesis hypothesis of depression was originally formed upon the demonstration that stress impacts levels of adult neurogenesis in the hippocampus. Since then much work has established that newborn neurons in the dentate gyrus are required for mediating some of the beneficial effects of antidepressant treatment. Recent studies combining behavioral, molecular and electrophysiological approaches have attempted to make sense of the role young neurons play in modulating mood by demonstrating a potential role in regulating the circuitry in the brain that underlies depression. Here we discuss the work that led to the neurogenesis hypothesis of depression, and the subsequent studies that have sought to test this hypothesis. We also discuss different animal models of depression that have been used to test the role of neurogenesis in mediating the antidepressant response.
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http://dx.doi.org/10.1111/j.1460-9568.2011.07614.xDOI Listing
March 2011

Dixdc1 is a critical regulator of DISC1 and embryonic cortical development.

Neuron 2010 Jul;67(1):33-48

Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

The psychiatric illness risk gene Disrupted in Schizophrenia-1 (DISC1) plays an important role in brain development; however, it is unclear how DISC1 is regulated during cortical development. Here, we report that DISC1 is regulated during embryonic neural progenitor proliferation and neuronal migration through an interaction with DIX domain containing-1 (Dixdc1), the third mammalian gene discovered to contain a Disheveled-Axin (DIX) domain. We determined that Dixdc1 functionally interacts with DISC1 to regulate neural progenitor proliferation by co-modulating Wnt-GSK3beta/beta-catenin signaling. However, DISC1 and Dixdc1 do not regulate migration via this pathway. During neuronal migration, we discovered that phosphorylation of Dixdc1 by cyclin-dependent kinase 5 (Cdk5) facilitates its interaction with the DISC1-binding partner Ndel1. Furthermore, Dixdc1 phosphorylation and its interaction with DISC1/Ndel1 in vivo is required for neuronal migration. Together, these data reveal that Dixdc1 integrates DISC1 into Wnt-GSK3beta/beta-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.neuron.2010.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938013PMC
July 2010
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