Increased Network Inhibition in the Dentate Gyrus of Adult Neuroligin-4 Knock-Out Mice

Abstract

Loss-of-function mutations in neuroligin-4 (Nlgn4), a member of the neuroligin family of postsynaptic adhesion proteins, cause autism spectrum disorder in humans. Nlgn4 knockout (KO) in mice leads to social behavior deficits and complex alterations of synaptic inhibition or excitation, depending on the brain region. In the present work, we comprehensively analyzed synaptic function and plasticity at the cellular and network levels in hippocampal dentate gyrus of Nlgn4 KO mice. Compared with wild-type littermates, adult Nlgn4 KO mice exhibited increased paired-pulse inhibition of dentate granule cell population spikes, but no impairments in excitatory synaptic transmission or short-term and long-term plasticityin vivo.In vitropatch-clamp recordings in neonatal organotypic entorhino-hippocampal slice cultures from Nlgn4 KO and wild-type littermates revealed no significant differences in excitatory or inhibitory synaptic transmission, homeostatic synaptic plasticity, and passive electrotonic properties in dentate granule cells, suggesting that the increased inhibitionin vivois the result of altered network activity in the adult Nlgn4 KO. A comparison with prior studies on Nlgn 1–3 knock-out mice reveals that each of the four neuroligins exerts a characteristic effect on both intrinsic cellular and network activity in the dentate gyrusin vivo.

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…A prior study has shown that the loss of Nlgn4 caused postsynaptic changes at inhibitory synapses and aberrant inhibitory neurotransmission, heavily disrupting γ-oscillations in the CA3 region of the mouse hippocampus ( 176 ). Unexpectedly, Muellerleile and colleagues discovered increased network inhibition within the dentate gyrus of adult Nlgn4 KO mice but unaltered in neonatal Nlgn4 KO mice ( 177 ). Guneykaya et al.…”