A Cellular and Molecular Basis for Social Behavior Deficits in Autism

Oral Presentation
Thursday, May 10, 2018: 2:52 PM
Willem Burger Hal (de Doelen ICC Rotterdam)
M. P. Anderson, Pathology and Neurology, Harvard Medical School/Beth Israel Deaconess Medical Center, Boston, MA
Background: Diverse genetic defects, immunological insults, and certain forms of epilepsy (infantile epileptic encephalopathies) are implicated in the pathogenesis of autism spectrum disorder (ASD). Maternal 15q11-13 triplications cause a highly penetrant autism with comorbid epilepsy that is linked to increased UBE3A dosages, a ubiquitin-ligase and transcriptional co-regulator. While the impressive deficits in sociability make them a core diagnostic criteria in ASD, the specific brain locus, neuronal cell-types, and molecular and cellular deficits in these circuits that give rise to this behavioral deficit have remained largely unknown.

Objectives: Define the neuronal circuit defects and molecular mechanisms whereby increased UBE3A and/or seizures impair sociability.

Methods: We combine a range of techniques including conditional genetic mouse models, genome-wide transcriptional profiling, protein interaction network analysis, conditional viral vectors, in vivo chemogenetics, and slice optogenetic electrophysiology with extensive behavioral analysis.

Results: Nuclear-confined increases of UBE3A impair sociability by repressing Cbln1 gene expression, a key node in an autism gene network of protein-protein interactions that trans-synaptically binds NRXN and GRID, two gene families frequently deleted in autism. Separately, epileptic seizures (causing activity-dependent Cbln1 repression) synergize with "asymptomatic" increases of Ube3a to impair sociability and do so through neurophysiological effects on glutamatergic neurons of the ventral tegmental area (VTA). Importantly, the seizures and UBE3A-induced sociability deficits are rescued by chemogenetic activation of, or Cbln1 delivery to, these brainstem VTA glutamatergic neurons.

Conclusions: Thus we show that experiencing seizures can uncover the effects of hidden asymptomatic gene mutations that make them prone to seizure-induced autism-related difficulties with social interaction. We also identify a major function of the enigmatic population of glutamatergic neurons in the brainstem VTA establishing their role as a key element of the neuronal circuitry that promotes sociability behavior. We also identify this brain locus and specialized cell-type as a major site where seizures and increased UBE3A synergize to impair sociability.