ABSTRACT
Mice mutant for the presynaptic protein Bassoon develop epileptic seizures and an altered pattern of neuronal activity that is accompanied by abnormal enlargement of several brain structures, with the strongest size increase in hippocampus and cortex. Using manganese-enhanced magnetic resonance imaging, an abnormal brain enlargement was found, which is first detected in the hippocampus 1 month after birth and amounts to an almost 40% size increase of this structure after 3 months. Stereological quantification of cell numbers revealed that enlargement of the dentate gyrus and the hippocampus proper is associated with larger numbers of principal neurons and of astrocytes. In search for the underlying mechanisms, an approximately 3-fold higher proportion of proliferation and survival of new-born cells in the dentate gyrus was found to go hand in hand with similarly larger numbers of doublecortin-positive cells and reduced numbers of apoptotic cells in the dentate gyrus and the hippocampus proper. Enlargement of the hippocampus and of other forebrain structures was accompanied by increased levels of brain-derived neurotrophic factor (BDNF). These data show that hippocampal overgrowth in Bassoon-mutant mice arises from a dysregulation of neurogenesis and apoptosis that might be associated with unbalanced BDNF levels.
Subject(s)
Apoptosis/physiology , Brain-Derived Neurotrophic Factor/metabolism , Dentate Gyrus/embryology , Nerve Tissue Proteins/metabolism , Neurogenesis/physiology , Animals , Astrocytes/metabolism , Cell Proliferation , Cell Survival/physiology , Dentate Gyrus/diagnostic imaging , Doublecortin Domain Proteins , Magnetic Resonance Imaging , Mice , Mice, Mutant Strains , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/metabolism , Nerve Tissue Proteins/genetics , Neurons/metabolism , Neuropeptides/genetics , Neuropeptides/metabolism , Organ Size/genetics , RadiographyABSTRACT
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.
