Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors

M Van Zandt; E Weiss; A Almyasheva; S Lipior; S Maisel; J R Naegele

doi:10.1016/j.bbr.2018.12.052

Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors

Behav Brain Res. 2019 Apr 19:362:7-20. doi: 10.1016/j.bbr.2018.12.052. Epub 2018 Dec 31.

Authors

M Van Zandt¹, E Weiss¹, A Almyasheva¹, S Lipior¹, S Maisel¹, J R Naegele²

Affiliations

¹ Wesleyan University, Department of Biology, Program in Neuroscience and Behavior, Middletown, CT, United States.
² Wesleyan University, Department of Biology, Program in Neuroscience and Behavior, Middletown, CT, United States. Electronic address: jnaegele@wesleyan.edu.

Abstract

The cell adhesion molecule neuroligin2 (NLGN2) regulates GABAergic synapse development, but its role in neural circuit function in the adult hippocampus is unclear. We investigated GABAergic synapses and hippocampus-dependent behaviors following viral-vector-mediated overexpression of NLGN2. Transducing hippocampal neurons with AAV-NLGN2 increased neuronal expression of NLGN2 and membrane localization of GABAergic postsynaptic proteins gephyrin and GABA_ARγ2, and presynaptic vesicular GABA transporter protein (VGAT) suggesting trans-synaptic enhancement of GABAergic synapses. In contrast, glutamatergic postsynaptic density protein-95 (PSD-95) and presynaptic vesicular glutamate transporter (VGLUT) protein were unaltered. Moreover, AAV-NLGN2 significantly increased parvalbumin immunoreactive (PV⁺) synaptic boutons co-localized with postsynaptic gephyrin⁺ puncta. Furthermore, these changes were demonstrated to lead to cognitive impairments as shown in a battery of hippocampal-dependent mnemonic tasks and social behaviors.

Keywords: Gephyrin; Neuroligin; Sociability; Social dominance; Spatial memory; VGAT.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Behavior, Animal / physiology*
Cell Adhesion Molecules, Neuronal / metabolism*
Hippocampus / metabolism*
Male
Mice, Inbred C57BL
Nerve Tissue Proteins / metabolism*
Neurons / physiology
Presynaptic Terminals / metabolism
Receptors, GABA-A / metabolism*
Synapses / metabolism*
Vesicular Inhibitory Amino Acid Transport Proteins
gamma-Aminobutyric Acid / metabolism

Substances

Cell Adhesion Molecules, Neuronal
Nerve Tissue Proteins
Receptors, GABA-A
Vesicular Inhibitory Amino Acid Transport Proteins
neuroligin 2
vesicular GABA transporter
gamma-Aminobutyric Acid

Grants and funding

R15 NS072879/NS/NINDS NIH HHS/United States