Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism.

Matthieu Hammer,Peter Jonas,Liam Patrick Tuffy,Nils Brose,Benjamin Hillman Cooper,Frederique Varoqueaux,Jeong-Seop Rhee,Holger Taschenberger,Hannelore Ehrenreich,Dilja Krueger-Burg,Sarit Pati Goswami

doi:10.1016/j.celrep.2015.09.011

Abstract

SummaryLoss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.

Highlights

Autism spectrum disorders (ASDs) are among the most prevalent neuropsychiatric disorders, with a high heritability that indicates a major role of genetic causes (Chen et al, 2015)
Loss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss
We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. These subtle synaptic changes are accompanied by pronounced perturbations of g-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders

Summary

Introduction

Autism spectrum disorders (ASDs) are among the most prevalent neuropsychiatric disorders, with a high heritability that indicates a major role of genetic causes (Chen et al, 2015). Nlgn deletion in mice causes aberrant inhibitory neurotransmission at retinal synapses (Hoon et al, 2011) While these findings are consistent with the notion that alterations in the balance of excitatory and inhibitory synaptic transmission play a role in ASD (Rubenstein and Merzenich, 2003; Yizhar et al, 2011), only minimal information is available on the function of Nlgn in forebrain regions relevant to ASD symptoms and phenotypes. We addressed this issue by assessing synaptic and network characteristics in Nlgn KO mice, focusing on the hippocampus as a model brain region with a key role in cognition and memory. Our data demonstrate that Nlgn co-determines the structure and function of perisomatic inhibitory synapses in hippocampal area CA3, and that the subtle synaptic consequences of Nlgn loss can have dramatic consequences on network functions related to cognition

Results

Discussion

Conclusion