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
Affiliations
Martina Sgritta
European Brain Research Institute (EBRI), 00161 Rome, Italy
Beatrice Vignoli
Department of Physics, University of Trento, Povo, 38123 TN, Italy
Domenico Pimpinella
European Brain Research Institute (EBRI), 00161 Rome, Italy
Marilena Griguoli
European Brain Research Institute (EBRI), 00161 Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council, 00185 Rome, Italy
Spartaco Santi
Institute of Molecular Genetics “Cavalli-Sforza”, National Research Council/IRCCS, Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
Andrzej Bialowas
Department of Neuroscience, International School for Advanced Studies (SISSA), 34136 Trieste, Italy
Grzegorz Wiera
Department of Neuroscience, International School for Advanced Studies (SISSA), 34136 Trieste, Italy
Paola Zacchi
Department of Life Sciences, University of Trieste, 34128 Trieste, Italy
Francesca Malerba
European Brain Research Institute (EBRI), 00161 Rome, Italy
Cristina Marchetti
European Brain Research Institute (EBRI), 00161 Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council, 00185 Rome, Italy
Marco Canossa
Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Povo, 38123 TN, Italy; Corresponding author
Enrico Cherubini
European Brain Research Institute (EBRI), 00161 Rome, Italy; Department of Neuroscience, International School for Advanced Studies (SISSA), 34136 Trieste, Italy; Corresponding author
Summary: 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 (NLG3R451C 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 NLG3R451C 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.
