TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy: Modulation by valproic acid

Veronica Ghiglieri, Carmelo Sgobio, Stefano Patassini, Vincenza Bagetta, Anna Fejtova, Carmela Giampá, Silvia Marinucci, Alexandra Heyden, Eckart D. Gundelfinger, Francesca R. Fusco, Paolo Calabresi, Barbara Picconi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1531-1540
Number of pages10
JournalNeuropsychopharmacology
Volume35
Issue number7
DOIs
Publication statusPublished - Jun 2010

Keywords

  • Bassoon mutant
  • Dorsolateral striatum
  • Electrophysiology
  • Medium spiny neurons
  • Parvalbumin-positive interneurons
  • Procedural learning

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'TrkB/BDNF-dependent striatal plasticity and behavior in a genetic model of epilepsy: Modulation by valproic acid'. Together they form a unique fingerprint.

Cite this