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Cholinergic neurons in the basal forebrain are involved in behavioral abnormalities associated with Cul3 deficiency:

Maximiliano Rapanelli1, Wei Wang1, Edward Hurley2,3

  • 1Department of Physiology and Biophysics, Jacobs School of Medicine, University at Buffalo, The State University of New York, Buffalo, USA.

Translational Psychiatry
|January 24, 2023
PubMed

Insights

Loss-of-function Cul3 gene mutations are linked to autism spectrum disorder (ASD). This study shows that cholinergic neuron dysfunction in the basal forebrain contributes to ASD-like behaviors and cognitive deficits.

Area of Science:

  • Neuroscience
  • Genetics
  • Developmental Biology

Background:

  • Loss-of-function mutations in the Cul3 gene are associated with autism spectrum disorder (ASD).
  • The precise pathogenic mechanisms linking Cul3 to ASD remain unclear.
  • Cholinergic system dysfunction is implicated in neurodevelopmental disorders.

Purpose of the Study:

  • To investigate the role of Cul3 in cholinergic neuron function.
  • To elucidate the contribution of basal forebrain (BF) cholinergic neurons to ASD-like phenotypes.
  • To explore therapeutic potential of modulating BF cholinergic activity.

Main Methods:

  • Conditional Cul3 ablation in mouse cholinergic neurons (ChatCRECul3F/+).
  • Assessment of social behavior, sensory gating, and cognitive function.
  • Chemogenetic manipulation of BF cholinergic neuron activity.

Main Results:

  • Cul3 ablation in cholinergic neurons induced ASD-like social and sensory gating deficits and cognitive impairments.
  • Inhibition of BF cholinergic neurons in healthy mice mimicked these deficits.
  • Stimulation of BF cholinergic neurons reversed sensory gating and cognitive abnormalities in Cul3-deficient mice.
  • Cortical hypofunction was observed, and BF-PFC cholinergic projections modulated cognitive deficits.

Conclusions:

  • Cholinergic dysfunction resulting from Cul3 deficiency contributes to ASD-like behavioral abnormalities.
  • Basal forebrain cholinergic neurons are critical for cognitive functions, particularly through their projections to the prefrontal cortex (PFC).
  • Targeting BF cholinergic neurons may offer a therapeutic strategy for ASD-related cognitive impairments.

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