Impaired synaptic plasticity in an animal model of autism exhibiting early hippocampal GABAergic-BDNF/TrkB signaling alterations

Martina Sgritta; Beatrice Vignoli; Domenico Pimpinella; Marilena Griguoli; Spartaco Santi; Andrzej Bialowas; Grzegorz Wiera; Paola Zacchi; Francesca Malerba; Cristina Marchetti; Marco Canossa; Enrico Cherubini

doi:10.1016/j.isci.2022.105728

Impaired synaptic plasticity in an animal model of autism exhibiting early hippocampal GABAergic-BDNF/TrkB signaling alterations

iScience. 2022 Dec 5;26(1):105728. doi: 10.1016/j.isci.2022.105728. eCollection 2023 Jan 20.

Authors

Martina Sgritta¹, Beatrice Vignoli², Domenico Pimpinella¹, Marilena Griguoli^{1

3}, Spartaco Santi⁴, Andrzej Bialowas⁵, Grzegorz Wiera⁵, Paola Zacchi⁶, Francesca Malerba¹, Cristina Marchetti^{1

3}, Marco Canossa⁷, Enrico Cherubini^{1

5}

Affiliations

¹ European Brain Research Institute (EBRI), 00161 Rome, Italy.
² Department of Physics, University of Trento, Povo, 38123 TN, Italy.
³ Institute of Molecular Biology and Pathology, National Research Council, 00185 Rome, Italy.
⁴ Institute of Molecular Genetics "Cavalli-Sforza", National Research Council/IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
⁵ Department of Neuroscience, International School for Advanced Studies (SISSA), 34136 Trieste, Italy.
⁶ Department of Life Sciences, University of Trieste, 34128 Trieste, Italy.
⁷ Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Povo, 38123 TN, Italy.

Abstract

In Neurodevelopmental Disorders, alterations of synaptic plasticity may trigger structural changes in neuronal circuits involved in cognitive functions. This hypothesis was tested in mice carrying the human R451C mutation of Nlgn3 gene (NLG3^R451C KI), found in some families with autistic children. To this aim, the spike time dependent plasticity (STDP) protocol was applied to immature GABAergic Mossy Fibers (MF)-CA3 connections in hippocampal slices from NLG3^R451C KI mice. These animals failed to exhibit STD-LTP, an effect that persisted in adulthood when these synapses became glutamatergic. Similar results were obtained in mice lacking the Nlgn3 gene (NLG3 KO mice), suggesting a loss of function. The loss of STD-LTP was associated with a premature shift of GABA from the depolarizing to the hyperpolarizing direction, a reduced BDNF availability and TrkB phosphorylation at potentiated synapses. These effects may constitute a general mechanism underlying cognitive deficits in those forms of Autism caused by synaptic dysfunctions.

Keywords: Cellular neuroscience; Developmental neuroscience; Neuroscience.