title: Modulation of network activity and induction of homeostatic synaptic plasticity by enzymatic removal of heparan sulfates.
abstract: Heparan sulfates (HSs) are complex and highly active molecules that are required for synaptogenesis and long-term potentiation. A deficit in HSs leads to autistic phenotype in mice. Here, we investigated the long-term effect of heparinase I, which digests highly sulfated HSs, on the spontaneous bioelectrical activity of neuronal networks in developing primary hippocampal cultures. We found that chronic heparinase treatment led to a significant reduction of the mean firing rate of neurons, particularly during the period of maximal neuronal activity. Furthermore, firing pattern in heparinase-treated cultures often appeared as epileptiform bursts, with long periods of inactivity between them. These changes in network activity were accompanied by an increase in the frequency and amplitude of miniature postsynaptic excitatory currents, which could be described by a linear up-scaling of current amplitudes. Biochemically, we observed an upregulation in the expression of the glutamate receptor subunit GluA1, but not GluA2, and a strong increase in autophosphorylation of α and β Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), without changes in the levels of kinase expression. These data suggest that a deficit in HSs triggers homeostatic synaptic plasticity and drastically affects functional maturation of neural network.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy Laboratory for Brain ECM Research, State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Korotchenko
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Cingolani
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kuznetsova
authors.affiliation: INSERM, U968, Paris 75012, France Sorbonne Universités, UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris 75012, France CNRS, UMR_7210, Paris 75012, France.
authors.forename: Luca Leonardo
authors.initials: LL
authors.lastname: Bologna
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Chiappalone
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy Laboratory for Brain ECM Research, State University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany alexander.dityatev@dzne.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005786:Gene Expression Regulation / Q000187:drug effects; D019763:Heparin Lyase / Q000378:metabolism* / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008839:Microelectrodes; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D018091:Receptors, AMPA / Q000378:metabolism
chemical_list: D019763:Heparin Lyase; D006497:Heparan Sulfate; D018091:Receptors, AMPA
keywords: AMPA receptor; burst; heparan sulfate proteoglycans; neural network; seizure; synaptic upscaling