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UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression.
bioRxiv. 2023 Mar 01B

Abstract

The circuit origins of aggression in autism spectrum disorder remain undefined. Here we report Tac1 -expressing glutamatergic neurons in ventrolateral division of ventromedial hypothalamus (VMHvl) drive intermale aggression. Aggression is increased due to increases of Ube3a gene dosage in the VMHvl neurons when modeling autism due to maternal 15q11-13 triplication. Targeted deletion of increased Ube3a copies 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 decreasing Cbln1 gene 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 presynaptic Nrxn1 or postsynaptic Grid1 (both ASD genes) to increase aggression. Targeted deletions of Grid1 in 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.

One Sentence Summary

A feedback circuit in the hypothalamus that inhibits aggression is impaired by converging autism genetic defects.

Links

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Authors

Nong Y
No affiliation info available
Stoppel DC
No affiliation info available
Johnson MA
No affiliation info available
Boillot M
No affiliation info available
Todorovic J
No affiliation info available
Shen J
No affiliation info available
Zhou X
No affiliation info available
Nadler MJS
No affiliation info available
Rodriguez C
No affiliation info available
Huo Y
No affiliation info available
Nagakura I
No affiliation info available
Kasper EM
No affiliation info available
Anderson MP
No affiliation info available

Pub Type(s)

Preprint

Language

eng

PubMed ID

36909588

Citation

Nong, Yi, et al. "UBE3A and Transsynaptic Complex NRXN1-CBLN1-GluD1 in a Hypothalamic VMHvl-arcuate Feedback Circuit Regulates Aggression." BioRxiv : the Preprint Server for Biology, 2023.
Nong Y, Stoppel DC, Johnson MA, et al. UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression. bioRxiv. 2023.
Nong, Y., Stoppel, D. C., Johnson, M. A., Boillot, M., Todorovic, J., Shen, J., Zhou, X., Nadler, M. J. S., Rodriguez, C., Huo, Y., Nagakura, I., Kasper, E. M., & Anderson, M. P. (2023). UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression. BioRxiv : the Preprint Server for Biology. https://doi.org/10.1101/2023.02.28.530462
Nong Y, et al. UBE3A and Transsynaptic Complex NRXN1-CBLN1-GluD1 in a Hypothalamic VMHvl-arcuate Feedback Circuit Regulates Aggression. bioRxiv. 2023 Mar 1; PubMed PMID: 36909588.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - UBE3A and transsynaptic complex NRXN1-CBLN1-GluD1 in a hypothalamic VMHvl-arcuate feedback circuit regulates aggression. AU - Nong,Yi, AU - Stoppel,David C, AU - Johnson,Mark A, AU - Boillot,Morgane, AU - Todorovic,Jelena, AU - Shen,Jason, AU - Zhou,Xinyu, AU - Nadler,Monica J S, AU - Rodriguez,Carrie, AU - Huo,Yuda, AU - Nagakura,Ikue, AU - Kasper,Ekkehard M, AU - Anderson,Matthew P, Y1 - 2023/03/01/ PY - 2023/3/13/entrez PY - 2023/3/14/pubmed PY - 2023/3/14/medline JF - bioRxiv : the preprint server for biology JO - bioRxiv N2 - : The circuit origins of aggression in autism spectrum disorder remain undefined. Here we report Tac1 -expressing glutamatergic neurons in ventrolateral division of ventromedial hypothalamus (VMHvl) drive intermale aggression. Aggression is increased due to increases of Ube3a gene dosage in the VMHvl neurons when modeling autism due to maternal 15q11-13 triplication. Targeted deletion of increased Ube3a copies 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 decreasing Cbln1 gene 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 presynaptic Nrxn1 or postsynaptic Grid1 (both ASD genes) to increase aggression. Targeted deletions of Grid1 in 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. One Sentence Summary: A feedback circuit in the hypothalamus that inhibits aggression is impaired by converging autism genetic defects. UR - https://www.unboundmedicine.com/medline/citation/36909588/UBE3A_and_transsynaptic_complex_NRXN1_CBLN1_GluD1_in_a_hypothalamic_VMHvl_arcuate_feedback_circuit_regulates_aggression_ DB - PRIME DP - Unbound Medicine ER -