Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability

Abstract

BTBR T+tf/J (BTBR) is an inbred strain of mice that displays prominent social deficits and repetitive behaviors analogous to the defining symptoms of autism, along with a complete congenital agenesis of corpus callosum. BTBR is genetically distant from the widely used C57BL/6J (B6) strain, which exhibits high levels of sociability, low repetitive behaviors, and an intact corpus callosum. Emerging evidence implicates compromised inter-hemispherical connectivity in some cases of autism. We investigated the hypothesis that the disconnection of corpus callosum (CC) fiber tracts contribute to behavioral traits in mice that are relevant to the behavioral symptoms of autism. Surgical lesion of the CC in B6 mice at postnatal day 7 had no effect on juvenile play and adult social approach, and did not elevate repetitive self-grooming. No correlations were detected between rostral-caudal extent of the CC lesion and behavioral scores. In addition, LP/J, the strain that is genetically closest to BTBR but has an intact CC, displayed juvenile play deficits and repetitive self-grooming similar to those seen in BTBR. These corroborative results offer evidence against the hypothesis that the corpus callosum disconnection is a primary cause of low sociability and high repetitive behaviors in inbred mice. Our findings indicate that genes mediating other aspects of neurodevelopment, including those whose mutations underlie more subtle disruptions in white matter pathways and connectivity, are more likely to contribute to the aberrant behavioral phenotypes in the BTBR mouse model of autism.

Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism

“…Normal 3-chambered social approach appeared in mice with mutations in genes including oxytocin [24], Shank1 [25], Nlgn2 [26], Ephrin-A [27] and 16p11.2 deletion [28] Variable findings on social approach across laboratories and in mouse lines generated on different genetic backgrounds have been reported for mutations including Fmr1 [29,30], Nlgn3 [31][32][33][34], and Nlgn4 [35,36]. Social deficits on the 3-chambered sociability have been wellreplicated in 2 inbred strains of mice, BTBR [10,12,[37][38][39][40][41][42][43][44] and Balb/cJ [45,46].…”

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

“…The effectiveness of ECT in BTBR mice is particularly remarkable considering that these animals have profound and irreversible deficiency in interhemispheric connectivity due to the missing corpus callosum and underdeveloped hippocampal commissure [41,42], which is congruent with compromised long-range connectivity in autism [43][44][45]. However, it should be noted that the lack of corpus callosum alone cannot explain the presence of autism-like behavior; indeed, postnatal mechanical lesion to the corpus callosum in LP/J mice (which are genetically close to BTBR mice but show no autism-like behavioral abnormalities) failed to produce autism-like impairments [46]. Concurrently with the compromised long-range connectivity, BTBR mice exhibit aberrant intrahemispheric connectivity as identified by diffusion tensor imaging [20], which is another widely acknowledged attribute of the autistic brain [47].…”

Hippocampal CA2 Region: A New Player in Social Dysfunctions

“…Similarly, reduction in parvalbumin immunoreactivity in CA2 [46,47], as well as AMPA [48] and histamine H3 receptors [49], was also observed in schizophrenia patients. Also in the 22q11.2 mouse line, Takahashi et al demonstrated that in contrast to wild-type mice, heterozygous pups used invariable vocal sequences with less complicated call types, which resulted in inefficient maternal approach [50]. This suggests that neonatal maternal care and social communication play a critical role in…”