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Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo

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Abstract

Neuroligins are transmembrane cell adhesion proteins with a key role in the regulation of excitatory and inhibitory synapses. Based on previous in vitro and ex vivo studies, neuroligin-1 (NL1) has been suggested to play a selective role in the function of glutamatergic synapses. However, the role of NL1 has not yet been investigated in the brain of live animals. We studied the effects of NL1-deficiency on synaptic transmission in the hippocampal dentate gyrus using field potential recordings evoked by perforant path stimulation in urethane-anesthetized NL1 knockout (KO) mice. We report that in NL1 KOs the activation of glutamatergic perforant path granule cell inputs resulted in reduced synaptic responses. In addition, NL1 KOs displayed impairment in long-term potentiation. Furthermore, field EPSP-population spike (E-S) coupling was greater in NL1 KO than WT mice and paired-pulse inhibition was reduced, indicating a compensatory rise of excitability in NL1 KO granule cells. Consistent with changes in excitatory transmission, NL1 KOs showed a significant reduction in hippocampal synaptosomal expression levels of the AMPA receptor subunit GluA2 and NMDA receptor subunits GluN1, GluN2A and GluN2B. Taken together, we provide first evidence that NL1 is essential for normal excitatory transmission and long-term synaptic plasticity in the hippocampus of intact animals. Our data provide insights into synaptic and circuit mechanisms of neuropsychiatric abnormalities such as learning deficits and autism.

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Acknowledgments

We thank Thomas Deller (Frankfurt, Germany) for continuous support and critical reading of the manuscript. The present work was supported by the LOEWE-Program “Neuronal Coordination Research Focus Frankfurt” (NeFF to S.W.S.), the Young Investigators Grant (from the Faculty of Medicine, Goethe-University, Frankfurt to P.J.), by the BMBF Grant (Germany-USA Collaboration in Computational Neuroscience to P.J., No. 01GQ1203A), the Max Planck Society, and the European Commission (EUROSPIN and SynSys consortia, N.B.). N.B. was further supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement No. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (Grant P7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and from Autism Speaks. DDK is a recipient of a fellowship of the Alexander von Humboldt Foundation and a Marie Curie International Reintegration Grant of the European Commission.

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Correspondence to Peter Jedlicka.

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P. Jedlicka and M. Vnencak are joint first authors.

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Jedlicka, P., Vnencak, M., Krueger, D.D. et al. Neuroligin-1 regulates excitatory synaptic transmission, LTP and EPSP-spike coupling in the dentate gyrus in vivo. Brain Struct Funct 220, 47–58 (2015). https://doi.org/10.1007/s00429-013-0636-1

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