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-typespecific 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.

Hippocampal enlargement in Bassoon-mutant mice is associated with enhanced neurogenesis, reduced apoptosis, and abnormal BDNF levels

“…Reloading of synaptic vesicles to the release sites is slowed significantly in the absence of functional Bassoon (Hallermann et al 2010). As a result, these mice suffer from recurrent rapidly generalizing seizures, indicating a general imbalance of excitatory and inhibitory neurotransmitter systems (Altrock et al 2003;Ghiglieri et al 2010). Volumetric magnetic resonance imaging (MRI) measurements have revealed that adult Bsn-mutant mice display an increased brain size caused primarily by the enlargement of the hippocampus and the cerebral cortex.…”

Ablation of the presynaptic organizer Bassoon in excitatory neurons retards dentate gyrus maturation and enhances learning performance

“…However, an in-depth behavioral assessment of the consequences of their disturbance in Bsn ΔEx4 / 5 mice is hampered by their visual and auditory impairment (Dick et al 2003 ; Khimich et al 2005 ) and the development of epilepsy (Altrock et al 2003 ). In initial experiments, an altered performance in a socially transmitted food preference task (Sgobio et al 2010 ) and an improved performance in a two-way active avoidance task that could be normalized by a TrkB antagonist (Ghiglieri et al 2010 ) were observed. However, the underlying cellular processes are difficult to address due to above-mentioned sensory impairments and potential gain of function effects by the residual Bassoon fragment lacking its central part, i.e., about two-thirds of the entire protein (Altrock et al 2003 ).…”

The Role for Alterations in Neuronal Activity in the Pathogenesis of Polyglutamine Repeat Disorders

“…There is some evidence to suggest that alterations in activitydependent secretion of neurotrophins, specifically the neurotrophin brain-derived neurotrophic factor (BDNF), are present in mouse models of disease. Because BDNF secretion in neurons is known to be regulated by neuronal activity [88][89][90], altered activity might be sufficient to produce pathologic changes in BDNF secretion. Indeed, there is emerging evidence for both HD and SCA1 that this may be the case.…”