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

Area of Science:

• Neuroscience
• Genetics
• Behavioral Science

Background:

• The neural basis of aggression in autism spectrum disorder (ASD) is not well understood.
• Identifying specific genes and neural circuits involved in ASD-related aggression is crucial for understanding its origins.

Approach:

• Investigated the role of Tac1-expressing glutamatergic neurons in the ventrolateral division of the ventromedial hypothalamus (VMHvl) in regulating aggression.
• Utilized mouse models of maternal 15q11-13 triplication, a genetic cause of ASD, to examine the impact of Ube3a gene dosage on aggression.
• Examined the synaptic connections between VMHvl neurons and arcuate nucleus AgRP/NPY neurons, focusing on the NRXN1-CBLN1-GluD1 transsynaptic complex.

Key Points:

• Increased Ube3a gene dosage in VMHvl neurons elevates male mouse aggression, mimicking aspects of ASD.
• Targeted deletion of excess Ube3a in VMHvl neurons reverses this heightened aggression.
• The UBE3A protein impairs the excitatory synapse between VMHvl and AgRP/NPY neurons by reducing Cbln1 expression.
• Activation of AgRP/NPY neurons inhibits VMHvl activity and suppresses aggression, highlighting a feedback mechanism.
• Synergistic effects of UBE3A with other ASD genes (Nrxn1, Grid1) on aggression were observed.

Conclusions:

• Multiple autism-associated genes converge on the VMHvl-arcuate AgRP/NPY glutamatergic synapse.
• Impaired excitation of AgRP/NPY feedback inhibitory neurons is a potential mechanism underlying increased aggression in genetic forms of autism.