Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy

Abstract

Temporal lobe epilepsy (TLE) in humans and animals is associated with axonal sprouting of glutamatergic neurons and neosynaptogenesis in the hippocampal formation. We examined whether this plasticity of excitatory pathways contributes to an increased level of glutamatergic excitation in the CA1 region of rats experiencing chronic spontaneous limbic seizures following kainic acid or pilocarpine treatment. In chronic cases, we report an extensive axonal sprouting of CA1 pyramidal neurons, with many axonal branches entering the pyramidal cell layer and stratum radiatum, regions that are not innervated by axonal collaterals of CA1 pyramidal neurons in control animals. Concurrently with this anatomical reorganization, a large increase of the spontaneous glutamatergic drive is observed in the dendrites and somata of CA1 pyramidal cells. Furthermore, electrical activation of the reorganized CA1 associational pathway evokes epileptiform bursts in CA1 pyramidal cells. These findings suggest that reactive plasticity could contribute to the hyperexcitability of CA1 pyramidal neurons and to the propagation of seizures in these two models of TLE.

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model

“…In contrast, CBD favoured a reduced firing of adapting, CCK interneurons that play a role in network modulation, as well as pyramidal cell firing, evidenced by a decrease in membrane time constant and input resistance in both the KA and Mg 2+ ‐free models. Incidentally, a significant loss of principal pyramidal neurons in both human and rodent epileptic hippocampi has been reported (Nadler et al, 1978; Babb et al, 1989), despite others reporting additional axonal sprouting of pyramidal cells, which will lead to enhancement of excitatory networks between pyramidal neurons, and probably explains the hyperactivity (Perez et al, 1996; Esclapez et al, 1999). Whether the CBD effects in reducing pyramidal cell hyperactivity reported here lead to a perseveration of pyramidal cell structure needs further investigation.…”

Altered Phase Precession and Compression of Temporal Sequences by Place Cells in Epileptic Rats

“…In addition to cell death, prolonged seizures in the adult brain leads to synaptic reorganization with aberrant growth (sprouting) of granule cell mossy fibers in the supragranular zone of the fascia and infrapyramidale region of CA3 (Sutula et al, 1988;Represa et al, 1994). Sprouting and neosynapse formation also occur in the CA1 pyramidal neurons, in which it has been shown that newly formed synapses produce an enhanced frequency of glutamatergic spontaneous synaptic currents (Esclapez et al, 1999) and the formation of novel aberrant kainatergic synapses on targets of mossy fibers (Epsztein et al, 2005). SE is also associated with dendritic loss of type A K ϩ channels in CA1 (Bernard et al, 2004), which results in heightened excitability.…”

Impaired hippocampal rhythmogenesis in a mouse model of mesial temporal lobe epilepsy

“…Indeed, in patients and in experimental models of mTLE, axonal sprouting was associated with the formation of new synapses (46,47). However, in the same cells, significant reduction in mEPSCs frequency was detected.…”