MeCP2 Deficiency Disrupts Activity-dependent Presynaptic Plasticity in the Mossy Fiber Projections in the Hippocampus

MARIA LAURA BERTOLDI; MARIA INÉS ZALOSNIK FIGUEROA; MARIA CAROLINA FABIO; SUSAN AJA; GERMAN A ROTH; GABRIELE RONNETT; ALICIA LAURA DEGANO

Frontiers in Cellular Neuroscience

Frontiers Media SA

Lugar: Lausanne ; Año: 2019

Methyl Cytosine Binding Protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression.Mutations in the gene encoding MeCP2 result in Rett Syndrome, (RTT) a pervasive neurodevelopmental disorder. RTT is one of fewAutism Spectrum Disorders (ASDs) whose cause was identified as a single gene mutation. Remarkably, abnormal levels of MeCP2have been associated to other neurodevelopmental disorders, as well as neuropsychiatric disorders. Therefore, many studies havebeen oriented to investigate the role of MeCP2 in the nervous system.In the present work, we explore cellular and molecular mechanisms affecting synaptic plasticity events in vivo in the hippocampusof MeCP2 mutant mice. While most studies addressed postsynaptic defects in the absence of MeCP2, we took advantage of an invivo activity-paradigm (seizures), two models of MeCP2 deficiency, and neurobiological assays to reveal novel defects inpresynaptic structural plasticity in the hippocampus in RTT rodent models. These approaches allowed us to determine that: MeCP2mutations alter presynaptic components, i. e., disrupts the plastic response of mossy fibers to synaptic activityand results inreduced axonal growth which is correlated with imbalanced trophic and guidance support, associated with aberrant expression ofBDNF and Sema3F. Our results also revealed that adult-born granule cells recapitulate maturational defects that have been onlyshown at early postnatal ages. As these cells do not mature timely, they may not integrate properly into the adult hippocampalcircuitry. Finally, we performed a hippocampal-dependent test that revealed defective spatial memory in these mice.Altogether, our studies establish a model that allows us to evaluate the effect of the manipulation of specific pathways involved inaxonal guidance, synaptogenesis, or maturation in specific circuits and correlate it with changes in behavior. Understanding themechanisms underlying the neuronal compromise caused by mutations in MeCP2 will provide information on the pathogenicmechanism of autistic spectrum disorders and improve our understanding of brain development and molecular basis of behavior