Publications by authors named "Melanie P Leussis"

14 Publications

  • Page 1 of 1

Disruption of the psychiatric risk gene Ankyrin 3 enhances microtubule dynamics through GSK3/CRMP2 signaling.

Transl Psychiatry 2018 07 25;8(1):135. Epub 2018 Jul 25.

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specific Ank3 isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus from Ank3+/- and Ank3+/+ mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, in Ank3+/- mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons from Ank3+/- mice revealed impaired elongation of microtubules. Using a CRISPR-dCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specific Ank3 increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specific Ank3 repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization in Ank3-repressed cells by lithium or CHIR99021, suggesting microtubule instability induced by Ank3 repression is dependent on CRMP2 activity. Taken together, our data indicate that ANK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.
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http://dx.doi.org/10.1038/s41398-018-0182-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060177PMC
July 2018

Lithium reverses behavioral and axonal transport-related changes associated with ANK3 bipolar disorder gene disruption.

Eur Neuropsychopharmacol 2017 03 18;27(3):274-288. Epub 2017 Jan 18.

Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK. Electronic address:

Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of Ank3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MS) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein-protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by Ank3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MS or highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in Ank3+/- mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MS followed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of Ank3+/- pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in Ank3+/- mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating Ank3-related psychiatric-related behavior.
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http://dx.doi.org/10.1016/j.euroneuro.2017.01.001DOI Listing
March 2017

The ankyrin-3 gene is associated with posttraumatic stress disorder and externalizing comorbidity.

Psychoneuroendocrinology 2013 Oct 21;38(10):2249-57. Epub 2013 Jun 21.

Biomedical Genetics, Department of Medicine, Boston University School of Medicine, Boston, MA, United States; Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States.

Background: The ankyrin 3 gene (ANK3) produces the ankyrin G protein that plays an integral role in regulating neuronal activity. Previous studies have linked ANK3 to bipolar disorder and schizophrenia. A recent mouse study suggests that ANK3 may regulate behavioral disinhibition and stress reactivity. This led us to hypothesize that ANK3 might also be associated with stress-related psychopathology such as posttraumatic stress disorder (PTSD), as well as disorders of the externalizing spectrum such as antisocial personality disorder and substance-related disorders that are etiologically linked to impulsivity and temperamental disinhibition.

Methods: We examined the possibility of association between ANK3 SNPs and both PTSD and externalizing (defined by a factor score representing a composite of adult antisociality and substance abuse) in a cohort of white non-Hispanic combat veterans and their intimate partners (n=554). Initially, we focused on rs9804190-a SNP previously reported to be associated with bipolar disorder, schizophrenia, and ankyrin G expression in brain. Then we examined 358 additional ANK3 SNPs utilizing a multiple-testing correction.

Results: rs9804190 was associated with both externalizing and PTSD (p=0.028 and p=0.042 respectively). Analysis of other ANK3 SNPs identified several that were more strongly associated with either trait. The most significant association with externalizing was observed at rs1049862 (p=0.00040, pcorrected=0.60). The most significant association with PTSD (p=0.00060, pcorrected=0.045) was found with three SNPs in complete linkage disequilibrium (LD)-rs28932171, rs11599164, and rs17208576.

Conclusions: These findings support a role of ANK3 in risk of stress-related and externalizing disorders, beyond its previous associations with bipolar disorder and schizophrenia.
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http://dx.doi.org/10.1016/j.psyneuen.2013.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775967PMC
October 2013

The ANK3 bipolar disorder gene regulates psychiatric-related behaviors that are modulated by lithium and stress.

Biol Psychiatry 2013 Apr 11;73(7):683-90. Epub 2012 Dec 11.

Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, USA.

Background: Ankyrin 3 (ANK3) has been strongly implicated as a risk gene for bipolar disorder (BD) by recent genome-wide association studies of patient populations. However, the genetic variants of ANK3 contributing to BD risk and their pathological function are unknown.

Methods: To gain insight into the potential disease relevance of ANK3, we examined the function of mouse Ank3 in the regulation of psychiatric-related behaviors using genetic, neurobiological, pharmacological, and gene-environment interaction (G×E) approaches. Ank3 expression was reduced in mouse brain either by viral-mediated RNA interference or through disruption of brain-specific Ank3 in a heterozygous knockout mouse.

Results: RNA interference of Ank3 in hippocampus dentate gyrus induced a highly specific and consistent phenotype marked by decreased anxiety-related behaviors and increased activity during the light phase, which were attenuated by chronic treatment with the mood stabilizer lithium. Similar behavioral alterations of reduced anxiety and increased motivation for reward were also exhibited by Ank3+/- heterozygous mice compared with wild-type Ank3+/+ mice. Remarkably, the behavioral traits of Ank3+/- mice transitioned to depression-related features after chronic stress, a trigger of mood episodes in BD. Ank3+/- mice also exhibited elevated serum corticosterone, suggesting that reduced Ank3 expression is associated with elevated stress reactivity.

Conclusions: This study defines a new role for Ank3 in the regulation of psychiatric-related behaviors and stress reactivity that lends support for its involvement in BD and establishes a general framework for determining the disease relevance of genes implicated by patient genome-wide association studies.
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http://dx.doi.org/10.1016/j.biopsych.2012.10.016DOI Listing
April 2013

Ankyrin 3: genetic association with bipolar disorder and relevance to disease pathophysiology.

Biol Mood Anxiety Disord 2012 Oct 1;2:18. Epub 2012 Oct 1.

Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.

Bipolar disorder (BD) is a multi-factorial disorder caused by genetic and environmental influences. It has a large genetic component, with heritability estimated between 59-93%. Recent genome-wide association studies (GWAS) using large BD patient populations have identified a number of genes with strong statistical evidence for association with susceptibility for BD. Among the most significant and replicated genes is ankyrin 3 (ANK3), a large gene that encodes multiple isoforms of the ankyrin G protein. This article reviews the current evidence for genetic association of ANK3 with BD, followed by a comprehensive overview of the known biology of the ankyrin G protein, focusing on its neural functions and their potential relevance to BD. Ankyrin G is a scaffold protein that is known to have many essential functions in the brain, although the mechanism by which it contributes to BD is unknown. These functions include organizational roles for subcellular domains in neurons including the axon initial segment and nodes of Ranvier, through which ankyrin G orchestrates the localization of key ion channels and GABAergic presynaptic terminals, as well as creating a diffusion barrier that limits transport into the axon and helps define axo-dendritic polarity. Ankyrin G is postulated to have similar structural and organizational roles at synaptic terminals. Finally, ankyrin G is implicated in both neurogenesis and neuroprotection. ANK3 and other BD risk genes participate in some of the same biological pathways and neural processes that highlight several mechanisms by which they may contribute to BD pathophysiology. Biological investigation in cellular and animal model systems will be critical for elucidating the mechanism through which ANK3 confers risk of BD. This knowledge is expected to lead to a better understanding of the brain abnormalities contributing to BD symptoms, and to potentially identify new targets for treatment and intervention approaches.
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http://dx.doi.org/10.1186/2045-5380-2-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492013PMC
October 2012

Depressive-like behavior in adolescents after maternal separation: sex differences, controllability, and GABA.

Dev Neurosci 2012 6;34(2-3):210-7. Epub 2012 Jul 6.

Laboratory of Developmental Psychopharmacology, Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA 02478, USA.

Exposure to adversity during development is an identified risk factor for depression later in life. In humans, early adversity accelerates the onset of depressive symptoms, which manifest during adolescence. Animal studies have used maternal separation as a model of early adversity to produce adult depressive-like behaviors, but have yet to examine these behaviors during adolescence. Moreover, the nature of depressive-like behaviors has not been well characterized in this model. Here, we used the triadic model of learned helplessness to understand controllability, helplessness, and motivational factors following maternal separation in male and female adolescent rats. We found sex-dependent changes in the effects of separation, with males demonstrating loss of controllability in an escapable shock condition, whereas females demonstrated motivational impairment in a no-shock condition. The effect, however, did not endure as adult females were no longer helpless. Reductions in parvalbumin, a GABAergic marker, in the prefrontal cortex of separated subjects relative to age-matched controls were evident and paralleled depressive-like behavior. Understanding the risk factors for depression, the nature of depressive-like behaviors, and their unique sex dependency may ultimately provide insight into improved treatments.
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http://dx.doi.org/10.1159/000339162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5267293PMC
February 2013

Abnormal behavioral and neurotrophic development in the younger sibling receiving less maternal care in a communal nursing paradigm in rats.

Psychoneuroendocrinology 2010 Apr 16;35(3):392-402. Epub 2009 Sep 16.

Section of Behavioural Neuroscience, Department of Cell Biology & Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy.

Maternal behavior in rodents has been proposed to vary as a function of the external environment and, in turn, adjust offspring's stress and fear responses. Early handling (brief periods of maternal separation during the first two weeks of life) studies and analyses of spontaneously high-caring rat mothers converge to indicate that increased levels of maternal care may reduce offspring emotionality in adulthood. However, the hypothesis that environment-dependent reduction in maternal care correlates with increased offspring vulnerability to pathology has been scarcely investigated. To test this hypothesis we studied maternal care and offspring development in young, adolescent and young-adult Sprague-Dawley rats reared in a communal nursing situation, characterized by two dams delivering their offspring four days apart and communally caring for them until weaning. We show that dams of the first-born litter show increased aggression towards the pregnant female and that offspring belonging to the second-born litter receive less maternal care compared to older cage-mates. Additionally, second-born rats show increased anxiety-related behavior in a plus-maze test in adolescence and adulthood and abnormal developmental trajectories in terms of social interaction and BDNF levels in the amygdala and hippocampus compared to both the first-born litter and to animal facility reared controls. This is the first indication that adverse environments, not requiring experimenter handling, may reduce maternal care and in turn increase offspring's emotionality and modify social behavior and BDNF developmental trajectories.
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http://dx.doi.org/10.1016/j.psyneuen.2009.07.016DOI Listing
April 2010

Quality of rearing guides expression of behavioral and neural seizure phenotypes in EL mice.

Brain Res 2009 Mar 18;1260:84-93. Epub 2009 Jan 18.

Department of Psychology, Boston College, Chestnut Hill, MA 02467, USA.

The present studies employed behavioral and neural markers of seizure-related plasticity to examine the relative contributions of genetic predisposition versus rearing environment in generating adult phenotypes in EL mice, a stress-induced animal model of epilepsy. Early environment was manipulated by cross-fostering pups of the EL strain to a seizure-resistant CD-1 control strain of mouse. The impact of changes in rearing quality on growth,exploratory and stress-reactivity phenotypes were examined, with a focus on the role of maternal care in shaping seizure susceptibility and neural cF os activation. Improvement in maternal care imposed by replacing biological EL dams with foster CD-1 mothers was sufficient to decrease pup mortality, to increase body weight gain (+0.1 g/day) and to delay the onset of seizure susceptibility in EL offspring beyond post-natal day 80–90. Moreover,hypoactivity in hippocampus and cortex among EL offspring cross-fostered to EL, but not CD-1 control, dams suggests that changes in rearing environment were accompanied by enduring changes in brain plasticity. Thus, neural and behavioral phenotypes of EL mice are dependent upon post-partum maternal care which if systematically enhanced can postpone seizure expression.
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http://dx.doi.org/10.1016/j.brainres.2009.01.007DOI Listing
March 2009

Attenuation of maternal behavior in virgin CD-1 mice by methylphenidate hydrochloride.

Physiol Behav 2008 Oct 12;95(3):395-9. Epub 2008 Jul 12.

Department of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4J1.

The administration of methylphenidate hydrochloride (MPH) to girls and women has increased in the last decade and the potential for mothers to receive this medication has also increased. Because substances that alter the dopaminergic systems can also disrupt maternal behavior, and MPH acts on dopaminergic neurons, we evaluated the influence of MPH on maternal behavior. The maternal induction paradigm allowed us to assess changes in spontaneous maternal behavior as a result of repeated exposure to MPH without exposing pups to the drug. Virgin female CD-1 mice received MPH (5 mg/kg) or saline daily, starting 3 days before pup exposure, and for the duration of the 10-day test period. Naïve groups of three pups were placed with the female each day and maternal behavior was assessed during 10-minute observation periods 1 h post-injection. MPH-treated females showed significantly less maternal behavior, including reduced pup licking and crouching over pups, compared to saline treated females. MPH-treated females also exhibited higher activity levels than saline treated females. Given the disruption in spontaneous maternal behavior of MPH-treated mice, further research examining the relationship between maternal behavior and MPH exposure is warranted.
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http://dx.doi.org/10.1016/j.physbeh.2008.07.010DOI Listing
October 2008

The enduring effects of an adolescent social stressor on synaptic density, part II: Poststress reversal of synaptic loss in the cortex by adinazolam and MK-801.

Synapse 2008 Mar;62(3):185-92

Laboratory for Developmental Neuropharmacology, Department of Psychiatry, Harvard Medical School and McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.

Experience programs synaptic development to match the needs of the environment. This process depends on the nature and timing of the experience. Exposure to stress during adolescence selectively reduces synaptic density in the prefrontal cortex (a later maturing region), while sparing hippocampal synapses (an earlier maturing region). To determine whether the anatomical effects of an adolescent social stressor in rats endures into adulthood and are reversible, male subjects were isolation or group housed between days 30 and 35 and then treated with vehicle, adinazolam, MK-801, or tianeptine between days 40 and 55. At day 60, immunohistochemistry revealed a 13.5% +/- 5.3% reduction in synaptophysin in the infralimbic cortex and cingulate gyrus in isolation-housed subjects. MK-801 and adinazolam restored cortical synaptic density to within 2% of group-housed values, suggesting that the synaptic loss induced by stress during adolescence is modulated through reduced glutamatergic activity directly by NMDA antagonism or indirectly by enhancing GABAergic activity. Tianeptine did not modulate adolescent stress effects in the prefrontal cortex. None of these drugs increased cortical synaptophysin in group-housed controls. Increased synaptophysin was observed in the group-housed condition in the hippocampus, striatum, and nucleus accumbens following drug exposure. Although stress did not decrease synaptic density in these regions, drug exposure failed to increase synaptic density when compared with the controls. Taken together, stress-induced changes in cortical, but not hippocampal, synaptic density initiated during adolescence endure into adulthood. These cortical changes can be reversed through a reduction of glutamatergic activity, but not serotonin augmentation.
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http://dx.doi.org/10.1002/syn.20483DOI Listing
March 2008

Seizure susceptibility and locus ceruleus activation are reduced following environmental enrichment in an animal model of epilepsy.

Epilepsy Behav 2008 Jan 5;12(1):30-8. Epub 2007 Nov 5.

Department of Psychology, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA.

Alterations in the complexity of social and physical housing environments modulate seizure susceptibility in animal models of epilepsy. The studies described here tested the hypothesis that environmental enrichment would delay seizure onset in the epileptic (El) mouse. Neural activation measured via cFos expression, accumulation of the stress neuropeptide corticotropin-releasing factor (CRF), and behavioral seizure susceptibility were quantified in El mice to better understand the mechanisms of ictogenesis. Enrichment housing of El mice from Postnatal Days 21 to 49 produced a 100% decrease in seizure susceptibility relative to El controls. cFos expression increased in the primary motor cortex, locus ceruleus, and hippocampus of El mice relative to ddY controls, an effect attenuated by enrichment housing. CRF levels were elevated by enrichment in the hippocampus of ddY mice only. This study provides evidence that enrichment housing delays the onset of seizure susceptibility in El mice while altering the neuronal and stress-related responses in seizure-associated regions of the El brain.
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http://dx.doi.org/10.1016/j.yebeh.2007.09.013DOI Listing
January 2008

Is adolescence a sensitive period for depression? Behavioral and neuroanatomical findings from a social stress model.

Synapse 2008 Jan;62(1):22-30

Laboratory of Developmental Neuropharmacology, Department of Psychiatry, Harvard Medical School and McLean Hospital, Belmont, Massachusetts 02478, USA.

Objectives: Sex differences in depressive symptoms emerge during adolescence, with females more at risk than males. However, adverse life events during development have greater impact on males. An animal model that incorporates behavioral and anatomical changes following adolescent stress is needed.

Experimental Design: Sprague-Dawley rats were exposed to social stress (SS; isolation housing during P30-35) or remained group-housed (GRP) and tested in the forced swim test (FST), the triadic learned helplessness model (LH), and the elevated plus maze. Western immunoblots of myelin basic protein (MBP) and synaptophysin (SVP) and spinophillin indexed synaptic and dendritic plasticity, respectively.

Principal Observations: At P36, SS increased climbing behavior in both sexes, and decreased the latency to immobility in females following a 15 min inescapable swim in the FST. Depressive-like behaviors were differentially elevated in both sexes 24 h later. GRP females exhibited higher levels of depression-related behaviors than GRP males in both FST and LH paradigms. SS significantly increased depressive behaviors in the FST in males, and impaired their ability to escape shock previously conditioned to be controllable. SS decreased open arm time in females only. The greatest reductions in synaptic plasticity proteins were observed in the prefrontal cortex: spinophillin (19.1%), SVP (7.9%), and MBP (48.7%, males only). Smaller reductions in spinophillin were observed in the hippocampus and amygdala.

Conclusions: Adolescent separation produces both behavioral and neural changes associated with stress-related depression and anxiety. Additional work is needed to improve our understanding of stress as it relates to depression during this vulnerable period of development.
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http://dx.doi.org/10.1002/syn.20462DOI Listing
January 2008

Habituation in rodents: a review of behavior, neurobiology, and genetics.

Neurosci Biobehav Rev 2006 13;30(7):1045-64. Epub 2006 Jun 13.

Laboratory of Developmental Neuropharmacology, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.

Habituation to a novel environment in rodents is commonly defined as a change in exploratory or locomotor activity over time (intrasession) or with repeated exposures (intersession). While numerous neuroactive substances are known to influence habituation, neurotransmitters that play particularly important roles are serotonin, acetylcholine, dopamine and glutamate. Although habituation is a complex process, studies over the past two decades have demonstrated that there is a genetic component. At present, although researchers are still attempting to isolate key genes that control habituation, findings in mutant mice have begun to highlight some of the genes that could play a role. The challenge will be in deciphering what genes are directly involved in the process of habituation, what genes indirectly influence habituation through a secondary mechanism, and what genes have no role in habituation but are only affected as part of the downstream cascade.
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http://dx.doi.org/10.1016/j.neubiorev.2006.03.006DOI Listing
November 2006

Routine tail suspension husbandry facilitates onset of seizure susceptibility in EL mice.

Epilepsia 2006 Apr;47(4):801-4

Department of Psychology, Boston College, Chestnut Hill, Massachusetts 02478, USA.

Purpose: Tail suspension can elicit seizures in susceptible EL mice, a model of idiopathic, multifactorial epilepsy. Further, repeated tail suspension hastens the lifetime onset of seizure susceptibility in these mice. The present study tested the hypothesis that curtailing human handling during development would delay the onset of seizure susceptibility relative to EL mice handled regularly by using tail suspension for standard laboratory husbandry.

Methods: Control mice were handled by the tail for bedding changes, whereas unhandled mice bedding was changed by using specially designed connector cages that allowed mice to transfer without handling to a cage containing clean bedding. Seizure susceptibility was tested beginning at 70, 80, 90, 100, or 140 days of age by using a handling-induced seizure-susceptibility paradigm.

Results: Among handled mice, more than half of the sample exhibited seizures by age 80 days relative to fewer than one fourth of unhandled mice. In addition, each group was tested a second time 10 days after the initial seizure-susceptibility test to detect potential experience-induced increases in seizure susceptibility. Once again, a higher frequency of handled mice expressed seizures at significantly younger ages relative to unhandled mice.

Conclusions: Although it was already known that repeated tail suspension could speed the onset of seizure susceptibility in EL mice, the present results are the first to demonstrate the converse finding that decreasing routine human handling can delay significantly the onset of seizure susceptibility. This suggests that removal of nonconsensual aspects of human-animal contact may delay or prevent the onset of seizure susceptibility.
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http://dx.doi.org/10.1111/j.1528-1167.2006.00525.xDOI Listing
April 2006