SHANK3 controls maturation of social reward circuits in the VTA

Abstract

SummaryHaploinsufficiency of SHANK3, encoding the synapse scaffolding protein SHANK3, leads to a highly penetrant form of Autism Spectrum Disorder (ASD). How SHANK3 insufficiency affects specific neural circuits and this is related to specific ASD symptoms remains elusive. Here we used shRNA to model Shank3 insufficiency in the Ventral Tegmental Area (VTA) of mice. We identified dopamine (DA) and GABA cell-type specific changes in excitatory synapse transmission that converge to reduce DA neuron activity and generate behavioral deficits, including impaired social preference. Administration of a positive allosteric modulator of the type 1 metabotropic glutamate receptors (mGluR1) during the first postnatal week restored DA neuron excitatory synapse transmission and rescued the social preference defects, while optogenetic DA neuron stimulation was sufficient to enhance social preference. Collectively, these data reveal the contribution of impaired VTA function to social behaviors and identify mGluR1 modulation during postnatal development as a potential treatment strategy.

Stress Impacts the Regulation Neuropeptides in the Rat Hippocampus and Prefrontal Cortex

“…Importantly, similar effects have been demonstrated when animals experience stress during neurodevelopmental periods, such as for example, peripubertal stress inhibits social interactions during adulthood. Stressors during both developmental periods and adulthood lead to changes in neuronal networks . It has thus been shown that peripubertal stress results in modulations of gene and cell adhesion molecule expression in prefrontal cortex (PFC) during adulthood, and adulthood stressors also modulate hippocampal functioning .…”

“…Stressors during both developmental periods and adulthood lead to changes in neuronal networks . It has thus been shown that peripubertal stress results in modulations of gene and cell adhesion molecule expression in prefrontal cortex (PFC) during adulthood, and adulthood stressors also modulate hippocampal functioning . Both hippocampus and PFC are also involved in cognitive and emotional processing of stress stimuli, and both hippocampus and PFC mediate the symptoms of depression and anxiety .…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…In addition, mGlu 1 knock out mice show disrupted prepulse inhibition similar to that seem with mGlu 5 knock out mice (Brody et al, 2003; Brody et al, 2004). Future studies with newly developed mGlu 1 tools (Cho et al, 2014; Lovell et al, 2013) will provide critical insights into the biological roles and therapeutic potential of mGlu 1 in treating schizophrenia, and other disorders in which mGlu 1 has been implicated, including ataxia, substance abuse, and autism spectrum disorders (Bariselli et al, 2016; Lum et al, 2014; Power et al, 2016). …”

VTA DA neuron excitatory synapses in Shank3 Δex4–9 mouse line

“…These synaptic changes occur together with reduced in vivo burst activity of DA neurons and behavioral deficits, including impaired social preference dynamics. Moreover, since post‐natal systemic treatment with a positive allosteric modulator (PAM) of mGluR1 rescued synaptic alterations and ameliorated neuronal activity and social deficits (Bariselli et al, ), we provided a link between altered DA neuron activity and social behavior. In fact, while synaptic deficits were also present at GABA neuron synapses, they were not rescued by PAM‐mGluR1 treatment and the optogenetic activation of VTA DA neurons was per sé sufficient to overcome shShank3‐induced behavioral impairment.…”

“…We have previously shown that the post‐natal downregulation of proline‐rich containing isoforms of SHANK3 changes synaptic properties onto DA neurons in the VTA (Bariselli et al, ). Animal models with constitutive mutations or deletion of the proline‐rich domain (Kouser et al, ; Speed et al, ) show decreased basal excitatory synaptic transmission in the hippocampus, but the AMPA and NMDA subunit composition has not been electrophysiologically analyzed.…”