Edward S. Brodkin

A mouse model system for genetic analysis of sociability : C57BL/6J versus BALB/cJ inbred mouse strains

BACKGROUND Impairments in social behaviors are highly disabling symptoms of autism, schizophrenia, and other psychiatric disorders. Mouse model systems are useful for identifying the many genes and environmental factors likely to affect complex behaviors, such as sociability (the tendency to seek social interaction). To progress toward developing such a model system, we tested the hypothesis that C57BL/6J inbred mice show higher levels of sociability than BALB/cJ inbred mice. METHODS Mice tested for sociability were 4- and 9-week-old, male and female C57BL/6J and BALB/cJ mice. On 2 consecutive days, the sociability of each test mouse toward an unfamiliar 4-week-old DBA/2J stimulus mouse was assessed with a social choice paradigm conducted in a three-chambered apparatus. Measures of sociability included the time that the test mouse spent near versus far from the stimulus mouse, the time spent directly sniffing the stimulus mouse, and the time spent in contact between test and stimulus mice in a free interaction. RESULTS C57BL/6J mice showed higher levels of sociability than BALB/cJ mice overall in each of these measures. CONCLUSIONS We propose that C57BL/6J and BALB/cJ mice will be a useful mouse model system for future genetic and neurobiological studies of sociability.

BALB/c mice: Low sociability and other phenotypes that may be relevant to autism

Low sociability is one of the most prominent and disabling symptoms of autism. The biology of sociability is not well understood, and there is no available treatment that adequately improves social functioning in most autistic patients. The development of animal models of reduced sociability can aid in the elucidation of the biology of social behaviors, and may ultimately shed light on the biology of autism. This paper will review evidence that mice of the BALB/c inbred strain show relatively low levels of social interaction in various settings and across various stages of development, including male-male interactions, female-female interactions, male-female sexual interactions, and parenting behaviors. Taken together, this evidence suggests a generally low level of sociability in BALB/c mice that may be relevant to autism. BALB/c mice also show other phenotypes with possible relevance to autism, including relatively high levels of anxiety and aggressive behaviors, large brain size, underdevelopment of the corpus callosum, and low levels of brain serotonin. Further research is needed to determine the relationship among these BALB/c phenotypes, and to determine their possible relevance to autism. In conclusion, the BALB/c inbred strain may be a useful animal model for identifying genes and neurobiological pathways involved in autism-related phenotypes.

Genetic variation in serotonin transporter alters resting brain function in healthy individuals.

BACKGROUND Perfusion functional magnetic resonance imaging (fMRI) was used to investigate the effect of genetic variation of the human serotonin transporter (5-HTT) gene (5-HTTLPR, SLC6A4) on resting brain function of healthy individuals. METHODS Twenty-six healthy subjects, half homozygous for the 5-HTTLPR short allele (s/s group) and half homozygous for the long allele (l/l group), underwent perfusion functional and structural magnetic resonance imaging during a resting state. The two genotype groups had no psychiatric illness and were similar in age, gender, and personality scores. RESULTS Compared with the l/l group, the s/s group showed significantly increased resting cerebral blood flow (CBF) in the amygdala and decreased CBF in the ventromedial prefrontal cortex. The effect of functional modulation in these regions by 5-HTTLPR genotype cannot be accounted for by variations in brain anatomy, personality, or self-reported mood. CONCLUSIONS The 5-HTTLPR genotype alters resting brain function in emotion-related regions in healthy individuals, including the amygdala and ventromedial prefrontal cortex. Such alterations suggest a broad role of the 5-HTT gene in brain function that may be associated with the genetic susceptibility for mood disorders such as depression.

Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice

Little is known about the genetics of social approach-avoidance behaviors. We measured social approach-avoidance of prepubescent female C57BL/6J, DBA/2J, FVB/NJ, AKR/J, A/J, and BALB/cJ mice towards prepubescent DBA/2J female mice. C57BL/6J mice showed the greatest predominance of approach, while BALB/cJ mice showed the greatest predominance of avoidance. Thus, this phenotype is affected by spontaneous genetic variation in mice and can be measured in an assay useful for future neurogenetic studies.

Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia.

N‐methyl‐D‐aspartate receptors (NMDARs) play a pivotal role in excitatory neurotransmission, synaptic plasticity and brain development. Clinical and experimental evidence suggests a dysregulation of NMDAR function and glutamatergic pathways in the pathophysiology of schizophrenia. We evaluated electrophysiological and behavioral properties of NMDAR deficiency utilizing mice that express only 5–10% of the normal level of NMDAR NR1 subunit. Auditory and visual event related potentials yielded significantly increased amplitudes for the P20 and N40 components in NMDAR deficient (NR1neo−/−) mice suggesting decreased inhibitory tone. Compared to wild types, NR1neo−/− mice spent less time in social interactions and showed reduced nest building. NR1neo−/− mice displayed a preference for open arms of a zero maze and central zone of an open field, possibly reflecting decreased anxiety‐related behavioral inhibition. However, locomotor activity did not differ between groups in either home cage environment or during behavioral testing. NR1neo−/− mice displayed hyperactivity only when placed in a large unfamiliar environment, suggesting that neither increased anxiety nor non‐specific motor activation accounts for differential behavioral patterns. Data suggest that NMDAR NR1 deficiency causes disinhibition in sensory processing as well as reduced behavioral inhibition and impaired social interactions. The behavioral signature in NR1neo−/− mice supports the impact of impaired NMDAR function in a mouse model with possible relevance to negative symptoms in schizophrenia.

Sertraline in adults with pervasive developmental disorders: a prospective open-label investigation.

The short-term efficacy and tolerability of sertraline for adults with pervasive developmental disorders (PDDs) were assessed in this investigation. Forty-two adults with PDDs (autistic disorder, N = 22; Aspergers disorder, N = 6; and PDD not otherwise specified [NOS], N = 14) participated in a 12-week, open-label, systematic trial of sertraline. Behavioral ratings of repetitive symptoms, aggression, and social relatedness were obtained at baseline and after 4, 8, and 12 weeks of sertraline administration. Twenty-four (57%) of 42 patients showed significant improvement, primarily in repetitive and aggressive symptoms. Statistically significant changes in measures of social relatedness did not occur. Patients with autistic disorder and PDD NOS did significantly better than those with Aspergers disorder. Based on global improvement item criteria from the Clinical Global Impression Scale, 15 of 22 (68%) patients with autistic disorder, none of six (0%) patients with Aspergers disorder, and 9 of 14 (64%) patients with PDD NOS were categorized as treatment responders. Sertraline was well tolerated; no adverse cardiovascular effects, extrapyramidal symptoms, or seizures were identified. These findings suggested that sertraline may be an effective treatment for interfering repetitive and aggressive symptoms in adults with PDDs. Definitive statements about the efficacy and tolerability of sertraline for treating adults with PDDs must await results from double-blind, placebo-controlled trials. These preliminary results should not be generalized to include children and adolescents with PDDs.

Neuregulin 1 Transgenic Mice Display Reduced Mismatch Negativity, Contextual Fear Conditioning and Social Interactions

INTRODUCTION Neuregulin-1 (NRG1) is one of susceptibility genes for schizophrenia and plays critical roles in glutamatergic, dopaminergic and GABAergic signaling. Using mutant mice heterozygous for Nrg1 (Nrg1(+/-)) we studied the effects of Nrg1 signaling on behavioral and electrophysiological measures relevant to schizophrenia. EXPERIMENTAL PROCEDURE Behavior of Nrg1(+/-) mice and their wild type littermates was evaluated using pre-pulse inhibition, contextual fear conditioning, novel object recognition, locomotor, and social choice paradigms. Event-related potentials (ERPs) were recorded to assess auditory gating and novel stimulus detection. RESULTS Gating of ERPs was unaffected in Nrg1(+/-) mice, but mismatch negativity in response to novel stimuli was attenuated. The Nrg1(+/-) mice exhibited behavioral deficits in contextual fear conditioning and social interactions, while locomotor activity, pre-pulse inhibition and novel object recognition were not impaired. SUMMARY Nrg1(+/-) mice had impairments in a subset of behavioral and electrophysiological tasks relevant to the negative/cognitive symptom domains of schizophrenia that are thought to be influenced by glutamatergic and dopaminergic neurotransmission. These mice are a valuable tool for studying endophenotypes of schizophrenia, but highlight that single genes cannot account for the complex pathophysiology of the disorder.

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.

Serotonin transporter genotype modulates amygdala activity during mood regulation

Recent studies have implicated the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) in depression vulnerability, particularly in the context of stress. Several neuroimaging studies have shown that 5-HTTLPR genotype predicts amygdala reactivity to negatively valenced stimuli, suggesting a mechanism whereby the short allele confers depression risk. The current study investigated whether 5-HTTLPR genotype similarly affects neural activity during an induced sad mood and during recovery from sad mood. Participants were 15 homozygous short (S) and 15 homozygous long (L) individuals. Regional cerebral blood flow was measured with perfusion functional magnetic resonance imaging during four scanning blocks: baseline, sad mood, mood recovery and following return to baseline. Comparing mood recovery to baseline, both whole brain analyses and template-based region-of-interest analyses revealed greater amygdala activity for the S vs the L-group. There were no significant amygdala differences found during the induced sad mood. These results demonstrate the effect of the S allele on amygdala activity during intentional mood regulation and suggest that amygdala hyperactivity during recovery from a sad mood may be one mechanism by which the S allele confers depression risk.

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

The identification of genetic variants regulating antidepressant response in human patients would allow for more individualized, rational, and successful drug treatments. We have previously identified the BALB/cJ inbred mouse strain as highly responsive to the selective serotonin reuptake inhibitor (SSRI) citalopram in the tail suspension test (TST), a widely used and well-established screening paradigm for detecting compounds with antidepressant activity. In contrast, A/J mice did not show a significant response to citalopram in this test despite exposure to equivalent plasma levels of the drug. To identify genetic determinants of this differential response, 506 F2 mice from an intercross between BALB/cJ and A/J mice were phenotyped. Composite interval mapping of 92 mice from the phenotypic extremes revealed three loci on chromosomes 7, 12, and 19 affecting citalopram response in the TST. The quantitative trait locus (QTL) at the telomeric end of chromosome 19 showed the greatest level of significance. Three candidate genes residing in this locus include those for vesicular monoamine transporter 2 (VMAT2, slc18a2), alpha 2A adrenergic receptor (adra2a), and beta 1 adrenergic receptor (adrb1). The protein coding regions of these three genes in BALB/cJ and A/J mice were sequenced and two polymorphisms were found in VMAT2 (Leu117Pro and Ser505Pro), while the transcribed regions of adra2a and adrb1 were of identical sequence between strains. Follow-up studies are needed to determine if the VMAT2 polymorphisms are functional and if they could explain the chromosome 19 QTL. The present quantitative trait study suggests possible candidate genes for human pharmacogenetic studies of therapeutic responses to SSRIs such as citalopram.