A Neuroligin-1 mutation associated with Alzheimer's disease produces memory and age-dependent impairments in hippocampal plasticity

Francisco Arias-Aragón; Enriqueta Tristán-Clavijo; Irene Martínez-Gallego; Estefanía Robles-Lanuza; Heriberto Coatl-Cuaya; Celia Martín-Cuevas; Ana C Sánchez-Hidalgo; Antonio Rodríguez-Moreno; Amalia Martinez-Mir; Francisco G Scholl

doi:10.1016/j.isci.2023.106868

A Neuroligin-1 mutation associated with Alzheimer's disease produces memory and age-dependent impairments in hippocampal plasticity

iScience. 2023 May 13;26(6):106868. doi: 10.1016/j.isci.2023.106868. eCollection 2023 Jun 16.

Authors

Affiliations

¹ Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.
² Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, 41009 Seville, Spain.
³ Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, 41013 Seville, Spain.

Abstract

Alzheimer's disease (AD) is characterized by memory impairments and age-dependent synapse loss. Experimental and clinical studies have shown decreased expression of the glutamatergic protein Neuroligin-1 (Nlgn1) in AD. However, the consequences of a sustained reduction of Nlgn1 are unknown. Here, we generated a knockin mouse that reproduces the NLGN1 Thr271fs mutation, identified in heterozygosis in a familial case of AD. We found that Nlgn1 Thr271fs mutation abolishes Nlgn1 expression in mouse brain. Importantly, heterozygous Nlgn1 Thr271fs mice showed delay-dependent amnesia for recognition memory. Electrophysiological recordings uncovered age-dependent impairments in basal synaptic transmission and long-term potentiation (LTP) in CA1 hippocampal neurons of heterozygous Nlgn1 Thr271fs mice. In contrast, homozygous Nlgn1 Thr271fs mice showed impaired fear-conditioning memory and normal basal synaptic transmission, suggesting unshared mechanisms for a partial or total loss of Nlgn1. These data suggest that decreased Nlgn1 may contribute to the synaptic and memory deficits in AD.

Keywords: Behavioral neuroscience; Cellular neuroscience; Molecular neuroscience.