Changes in vesicular transporters for γ‐aminobutyric acid and glutamate reveal vulnerability and reorganization of hippocampal neurons following pilocarpine‐induced seizures

Abstract

The reorganizations of the overall intrinsic glutamatergic and gamma-aminobutyric acid (GABA)-ergic hippocampal networks as well as the time course of these reorganizations during development of pilocarpine-induced temporal lobe epilepsy were studied with in situ hybridization and immunohistochemistry experiments for the vesicular glutamate transporter 1 (VGLUT1) and the vesicular GABA transporter (VGAT). These transporters are particularly interesting as specific markers for glutamatergic and GABAergic neurons, respectively, whose expression levels could reflect the demand for synaptic transmission and their average activity. We report that 1) concomitantly with the loss of some subpopulations of VGAT-containing neurons, there was an up-regulation of VGAT synthesis in all remaining GABA neurons as early as 1 week after pilocarpine injection. This enhanced synthesis is characterized by marked increases in the relative amount of VGAT mRNAs in interneurons associated with increased intensity of axon terminal labeling for VGAT in all hippocampal layers. 2) There was a striking loss of mossy cells during the latent period, demonstrated by a long-term decrease of VGLUT1 mRNA-containing hilar neurons and associated loss of VGLUT1-containing terminals in the dentate gyrus inner molecular layer. 3) There were aberrant VGLUT1-containing terminals at the chronic stage resulting from axonal sprouting of granule and pyramidal cells. This is illustrated by a recovery of VGLUT1 immunoreactivity in the inner molecular layer and an increased VGLUT1 immunolabeling in the CA1-CA3 dendritic layers. These data indicate that an increased activity of remaining GABAergic interneurons occurs during the latent period, in parallel with the loss of vulnerable glutamatergic and GABAergic neurons preceding the reorganization of glutamatergic networks.

Early Deficits in Spatial Memory and Theta Rhythm in Experimental Temporal Lobe Epilepsy

“…S4, available at www.jneurosci.org as supplemental material) and of a major cell loss in this model. The pattern of neuronal damage observed in the hippocampus and dentate gyrus in pilocarpine-treated animals after a 40-min-long SE was very similar to that described previously in pilocarpine-treated animals after 2-3-h-long SE (Obenaus et al, 1993;Esclapez et al, 1999;Dinocourt et al, 2003;Boulland et al, 2007). It included a cell loss restricted to the hilus of the dentate gyrus and stratum oriens of CA1 that contrasts with a good preservation of neurons in all other layers of the hippocampus and dentate gyrus including the CA1-CA3 pyramidal cells and dentate granule cell layers (supplemental Fig.…”

Altered vesicular glutamate transporter expression in human temporal lobe epilepsy with hippocampal sclerosis

“…As such, changes in VGLUT expression can be reflected in their projection region (i.e., hippocampus) at the protein level, but not necessarily at the mRNA level. This kind of discrepancy between protein and mRNA expression levels has already been described for VGLUT1 in both human and animal pathological tissue [4,11]. Noteworthy, a strong trend toward increased VGLUT3 mRNA expression levels is observed.…”

Cracking Down on Inhibition: Selective Removal of GABAergic Interneurons from Hippocampal Networks

“…Sustained failure of GABAergic neurotransmission in, e.g., temporal lobe epilepsy, induces the progressive loss of pyramidal cells in CA subfields, as well as dispersion of dentate granule cells (Boulland et al, 2007;Antonucci et al, 2008). Although VGLUT1 ϩ hippocampal afferents remained preserved (Fig.…”