TY - JOUR
T1 - MeCP2 deficiency disrupts kainate-induced presynaptic plasticity in the mossy fiber projections in the hippocampus
AU - Bertoldi, Maria Laura
AU - Zalosnik, Maria Ines
AU - Fabio, Maria Carolina
AU - Aja, Susan
AU - Roth, German A.
AU - Ronnett, Gabriele V.
AU - Degano, Alicia L.
N1 - Funding Information:
This work was supported by Consejo Nacional de Investigaciones Científicas y Técnicas de la República Argentina (CONICET, to AD), Secretaria de Ciencia y Tecnología-Universidad Nacional de Córdoba (SeCyT-UNC, to AD), Agencia Nacional de Promoción Científica y Técnológica (FONCyT-PICT 2013 No. 106, to AD), International Society for Neurochemistry (ISN-CAEN, to AD and MB), and by a Research with the Daegu Gyeongbuk Institute of Science and Technology (DGIST) Convergence Science Center, funded by grant #10-BD-04 from Korean Ministry of Education, Science, and Technology (to SA and GVR).
Publisher Copyright:
© 2019 Bertoldi, Zalosnik, Fabio, Aja, Roth, Ronnett and Degano.
PY - 2019/5/14
Y1 - 2019/5/14
N2 - 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 few autism spectrum disorders whose cause was identified as a single gene mutation. Remarkably, abnormal levels of MeCP2 have been associated to other neurodevelopmental disorders, as well as neuropsychiatric disorders. Therefore, many studies have been 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 hippocampus of MeCP2 mutant mice. While most studies addressed postsynaptic defects in the absence of MeCP2, we took advantage of an in vivo activity-paradigm (seizures), two models of MeCP2 deficiency, and neurobiological assays to reveal novel defects in presynaptic structural plasticity in the hippocampus in RTT rodent models. These approaches allowed us to determine that MeCP2 mutations alter presynaptic components, i.e., disrupts the plastic response of mossy fibers to synaptic activity and results in reduced axonal growth which is correlated with imbalanced trophic and guidance support, associated with aberrant expression of brain-derived neurotrophic factor and semaphorin 3F. Our results also revealed that adult-born granule cells recapitulate maturational defects that have been only shown at early postnatal ages. As these cells do not mature timely, they may not integrate properly into the adult hippocampal circuitry. 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 in axonal guidance, synaptogenesis, or maturation in specific circuits and correlate it with changes in behavior. Understanding the mechanisms underlying the neuronal compromise caused by mutations in MeCP2 could provide information on the pathogenic mechanism of autistic spectrum disorders and improve our understanding of brain development and molecular basis of behavior.
AB - 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 few autism spectrum disorders whose cause was identified as a single gene mutation. Remarkably, abnormal levels of MeCP2 have been associated to other neurodevelopmental disorders, as well as neuropsychiatric disorders. Therefore, many studies have been 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 hippocampus of MeCP2 mutant mice. While most studies addressed postsynaptic defects in the absence of MeCP2, we took advantage of an in vivo activity-paradigm (seizures), two models of MeCP2 deficiency, and neurobiological assays to reveal novel defects in presynaptic structural plasticity in the hippocampus in RTT rodent models. These approaches allowed us to determine that MeCP2 mutations alter presynaptic components, i.e., disrupts the plastic response of mossy fibers to synaptic activity and results in reduced axonal growth which is correlated with imbalanced trophic and guidance support, associated with aberrant expression of brain-derived neurotrophic factor and semaphorin 3F. Our results also revealed that adult-born granule cells recapitulate maturational defects that have been only shown at early postnatal ages. As these cells do not mature timely, they may not integrate properly into the adult hippocampal circuitry. 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 in axonal guidance, synaptogenesis, or maturation in specific circuits and correlate it with changes in behavior. Understanding the mechanisms underlying the neuronal compromise caused by mutations in MeCP2 could provide information on the pathogenic mechanism of autistic spectrum disorders and improve our understanding of brain development and molecular basis of behavior.
KW - Activity-dependent gene expression
KW - Autism
KW - MeCP2
KW - Neurogenesis
KW - Presynaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=85068440530&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068440530&partnerID=8YFLogxK
U2 - 10.3389/fncel.2019.00286
DO - 10.3389/fncel.2019.00286
M3 - Article
C2 - 31333414
AN - SCOPUS:85068440530
VL - 13
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 286
ER -