β-catenin deficiency in forebrain excitatory neurons induces fear memory deficits and physiological alterations.

Overview

1. Department of Physiology and Biophysics, State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA

Abstract

β-catenin-coding gene CTNNB1 is a top-ranking risk gene for autism and intellectual disability. To better understand how CTNNB1 haploinsufficiency is involved in the pathophysiology of neurodevelopmental disorders, we generated a new mouse model that enables Ctnnb1 deletion in forebrain excitatory neurons starting at embryonic corticogenesis. Behavioural assays of the Ctnnb1 conditional knockout (cKO) mice revealed significant fear memory deficits, despite normal social preference, anxiety, spatial and recognition memory. Pyramidal neurons in prefrontal cortex (PFC) of Ctnnb1 cKO mice exhibited the significantly elevated intrinsic excitability but markedly decreased AMPA receptor-mediated synaptic response, while GABAA or NMDA receptor-mediated synaptic response was unchanged. Gene profiling revealed the significantly reduced mRNA level of Syp (encoding Synaptophysin) and Nlng2 (encoding Neuroligin-2) in PFC of Ctnnb1 cKO mice, while most of other screened genes were unchanged. These results suggest that β-catenin deficiency in forebrain excitatory neurons leads to fear conditioning impairment, which could be contributed by the diminished excitatory synaptic transmission in PFC resulting from disrupted synaptic gene expression.

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Data availability

Data will be made available on request. The software code for electrophysiological data analyses has been uploaded to Dryad. The link is: https://doi.org/10.5061/dryad.kh18932pg.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 5 keywords, 1 funder, 77 references.

Cite

This paper

Hernandez Carballo, L. G., Senek, R., Novototskaya-Vlasova, K., Li, P., Pletnikov, M., & Yan, Z. (2026). β-catenin deficiency in forebrain excitatory neurons induces fear memory deficits and physiological alterations. Brain communications, 8(4), fcag286. https://doi.org/10.1093/braincomms/fcag286

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