title: TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy: modulation by valproic acid.
abstract: In mice lacking the central domain of the presynaptic scaffold Bassoon the occurrence of repeated cortical seizures induces cell-type-specific plasticity changes resulting in a general enhancement of the feedforward inhibition within the striatal microcircuit. Early antiepileptic treatment with valproic acid (VPA) reduces epileptic attacks, inhibits the emergence of pathological form of plasticity in fast-spiking (FS) interneurons and restores physiological striatal synaptic plasticity in medium spiny (MS) neurons. Brain-derived neurotrophic factor (BDNF) is a key factor for the induction and maintenance of synaptic plasticity and it is also implicated in the mechanisms underlying epilepsy-induced adaptive changes. In this study, we explore the possibility that the TrkB/BDNF system is involved in the striatal modifications associated with the Bassoon gene (Bsn) mutation. In epileptic mice abnormal striatum-dependent learning was paralleled by higher TrkB levels and an altered distribution of BDNF. Accordingly, subchronic intrastriatal administration of k252a, an inhibitor of TrkB receptor tyrosine kinase activity, reversed behavioral alterations in Bsn mutant mice. In addition, in vitro manipulations of the TrkB/BDNF complex by k252a, prevented the emergence of pathological plasticity in FS interneurons. Chronic treatment with VPA, by reducing seizures, was able to rebalance TrkB to control levels favoring a physiological redistribution of BDNF between MS neurons and FS interneurons with a concomitant recovery of striatal plasticity. Our results provide the first indication that BDNF is involved in determining the striatal alterations occurring in the early-onset epileptic syndrome associated with the absence of presynaptic protein Bassoon.
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.forename: Carmelo
authors.initials: C
authors.lastname: Sgobio
authors.forename: Stefano
authors.initials: S
authors.lastname: Patassini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Bagetta
authors.forename: Anna
authors.initials: A
authors.lastname: Fejtova
authors.forename: Carmela
authors.initials: C
authors.lastname: Giampà
authors.forename: Silvia
authors.initials: S
authors.lastname: Marinucci
authors.forename: Alexandra
authors.initials: A
authors.lastname: Heyden
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.forename: Francesca R
authors.initials: FR
authors.lastname: Fusco
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D064026:Calbindins; D002227:Carbazoles / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D026121:Indole Alkaloids / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D020813:Receptor, trkB / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; C498441:Bsn protein, mouse; D064026:Calbindins; D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D014635:Valproic Acid; C049985:staurosporine aglycone; D020813:Receptor, trkB