Autism spectrum disorder (ASD) is characterized by its deficits in social interactions. Oxytocin is a hypothalamic neuropeptide known to increase social interactions through its oxytocin receptor (Oxtr) but where this occurs remains undefined. Maternal 15q11-13 triplications (extranumerary isodicentric chromosome 15, idic15) cause a highly penetrant autism that we have linked to the increased dosage of UBE3A. UBE3A encodes an ubiquitin-ligase and transcriptional co-regulator expressed exclusively from the maternal allele in mature neurons. Seizures are a frequent comorbidity in ASD including in idic15. In our recent study (Krishnan et al. Nature 2017), we established that a previously enigmatic population of glutamatergic neurons in the brainstem ventral tegmental area (VTA) drives sociability and found increases of UBE3A and seizures converge to repress expression of autism network gene Cbln1 to impair sociability within these neurons.
In Aim 1, we investigate a new concept, that oxytocin receptors mark the specific population of VTA glutamatergic neurons that promote sociability and that oxytocin receptor activity in these neurons is necessary for normal sociability.
In Aim 2, we investigate the target site where VTA glutamatergic neurons promote sociability by testing if chemogenetically-controlled activity and Grid1 expression (Cbln1's postsynaptic binding partner that is deleted in autism) in the nucleus accumbens are necessary and sufficient to promote sociability. VTA glutamatergic neurons form excitatory synapses onto nucleus accumbens neurons and we have shown these synapses are impaired by Cbln1 deletion and by seizures.
In Aim 3, we test if increases of UBE3A and seizures converge on the specific VTA glutamatergic neurons that express oxytocin receptors to impair sociability and glutamategic transmission if these defects can rescued by adding back Cbln1 to these specialized neurons.
In Aim 4, we investigate whether in vivo chemogenetic increases of oxytocin signaling can rescue the VTA glutamatergic neuron to nucleus accumbens synaptic defects and sociability impairments produced by increased UBE3A and seizures. In this study, we combine conditional mouse genetics, stereotaxic viral vector-based gene deliveries methods including VGluT2 and Oxtr promoter intersectional genetics, behavioral chemogenetics, and brain slice optogenetics electrophysiology techniques to uncover a convergent molecular autism gene network and neuronal circuitry where three models of human autism spectrum disorder impair sociability. (1) Increased Ube3a gene dosage (maternal 15q11-13 triplication) and (2) epilepsy convergence to repress Cbln1 in VTA glutamatergic neurons and (3) loss of Grid1, Cbln1's postsynaptic binding partner in nucleus accumbens all impair sociability. We also perform a series of in vivo preclinical tests of the efficacy of therapeutic interventions using viral vector-based methods aimed at these molecules and circuits and the oxytocin system.

Public Health Relevance

Autism spectrum disorder (ASD) is a heterogeneous group of related behavioral disorders, characterized by deficits in social behaviors and increased repetitive behaviors. This project seeks to learn how increases of Ube3a, a gene within a frequent genetic copy number variant found in human ASD (maternal 15q11-13 duplication) affects the function of specific neurons in the midbrain to impair sociability. Understanding the genetic and circuit defects that underlie impaired sociability, a core deficit in ASD, will provide therapeutic targets to treat the deficit.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH112714-03
Application #
9856154
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Simmons, Janine M
Project Start
2018-05-01
Project End
2023-01-31
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Anderson, Matthew P (2018) DEPDC5 takes a second hit in familial focal epilepsy. J Clin Invest 128:2194-2196