UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression

Abstract

The circuit origins of aggression in autism spectrum disorder remain undefined. Here we reportTac1-expressing glutamatergic neurons in ventrolateral division of ventromedial hypothalamus (VMHvl) drive intermale aggression. Aggression is increased due to increases ofUbe3agene dosage in the VMHvl neurons when modeling autism due to maternal 15q11-13 triplication. Targeted deletion of increasedUbe3acopies in VMHvl reverses the elevated aggression adult mice. VMHvl neurons form excitatory synapses onto hypothalamic arcuate nucleus AgRP/NPY neurons through a NRXN1-CBLN1-GluD1 transsynaptic complex and UBE3A impairs this synapse by decreasingCbln1gene expression. Exciting AgRP/NPY arcuate neurons leads to feedback inhibition of VMHvl neurons and inhibits aggression. Asymptomatic increases of UBE3A synergize with a heterozygous deficiency of presynapticNrxn1or postsynapticGrid1(both ASD genes) to increase aggression. Targeted deletions ofGrid1in arcuate AgRP neurons impairs the VMHvl to AgRP/NPY neuron excitatory synapses while increasing aggression. Chemogenetic/optogenetic activation of arcuate AgRP/NPY neurons inhibits VMHvl neurons and represses aggression. These data reveal that multiple autism genes converge to regulate the VMHvl-arcuate AgRP/NPY glutamatergic synapse. The hypothalamic circuitry implicated by these data suggest impaired excitation of AgRP/NPY feedback inhibitory neurons may explain the increased aggression behavior found in genetic forms of autism.

<i>Grid1</i> regulates the onset of puberty in female rats

“…Grid1 is widely distributed in the brain of adult mice, cavies and rats [13] and has been found to be involved in the glutamatergic signaling pathway, which directly regulates GnRH [10]. Grid1 is associated with synapse formation [29,37] and recent studies have shown that multiple genetic forms of ASD disrupt VMHvl-arcuate AgRP/NPY neuron glutamate synapses [25]. Dinesh et al indicated that GluD1 may contribute to developmental disorders through the autophagy pathway [6].…”