Cholinergic Neurons in the Basal Forebrain Are Involved in Behavioral Abnormalities Associated with Cul3 Deficiency: Role of Prefrontal Cortex Projections in Cognitive Deficits

Overview

Journal Transl Psychiatry

Specialties Psychiatry
Public Health

Date 2023 Jan 24

PMID 36693858

Authors

Maximiliano Rapanelli

Wei Wang

Edward Hurley

Maria Laura Feltri

Christopher Pittenger

Luciana Romina Frick

Zhen Yan

Affiliations

Soon will be listed here.

Abstract

Loss-of-function mutations of the gene Cul3 have been identified as a risk factor for autism-spectrum disorder (ASD), but the pathogenic mechanisms are not well understood. Conditional Cul3 ablation in cholinergic neurons of mice (ChatCul3) recapitulated ASD-like social and sensory gating phenotypes and caused significant cognitive impairments, with diminished activity of cholinergic neurons in the basal forebrain (BF). Chemogenetic inhibition of BF cholinergic neurons in healthy mice induced similar social and cognitive deficits. Conversely, chemogenetic stimulation of BF cholinergic neurons in ChatCul3 mice reversed abnormalities in sensory gating and cognition. Cortical hypofunction was also found after ChAT-specific Cul3 ablation and stimulation of cholinergic projections from the BF to the prefrontal cortex (PFC) mitigated cognitive deficits. Overall, we demonstrate that cholinergic dysfunction due to Cul3 deficiency is involved in ASD-like behavioral abnormalities, and that BF cholinergic neurons are particularly critical for cognitive component through their projections to the PFC.

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