Upregulation of Cholinergic Modulators Lypd6 and Lypd6b Associated with Autism Drives Anxiety and Cognitive Decline

Overview

Journal Cell Death Discov

Date 2024 Oct 21

PMID 39433742

Authors

Aizek B Isaev

Maxim L Bychkov

Dmitrii S Kulbatskii

Alexander A Andreev-Andrievskiy

Mikhail A Mashkin

Mikhail A Shulepko

Olga V Shlepova

Eugene V Loktyushov

Alexander V Latanov

Mikhail P Kirpichnikov

Ekaterina N Lyukmanova

Affiliations

Soon will be listed here.

Abstract

Intellectual disability and autistic features are associated with chromosome region 2q23.q23.2 duplication carrying LYPD6 and LYPD6B genes. Here, we analyzed LYPD6 and LYPD6B expression in patients with different neuropsychiatric disorders. Increased LYPD6 and LYPD6B expression was revealed in autism and other disorders. To study possible consequences of Lypd6 and Lypd6b overexpression in the brain, we used a mouse model with intracerebroventricular delivery of recombinant analogs of these proteins. A two-week infusion evoked significant memory impairment and acute stress. Both modulators downregulated hippocampal and amygdala dendritic spine density. No changes in synaptic plasticity were observed. Intracerebroventricular administration by both proteins downregulated hippocampal expression of Lypd6, Lypd6b, and α7 nicotinic acetylcholine receptor (nAChR). Similar to Lypd6, Lypd6b targeted different nAChR subtypes in the brain with preferential inhibition of α7- and α4β2-nAChRs. Thus, increased Lypd6 and Lypd6b level in the brain are linked to cholinergic system depression, neuronal atrophy, memory decline, and anxiety.

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