Kindling induces transient fast inhibition in the dentate gyrus–CA3 projection

Abstract

The granule cells of the dentate gyrus (DG) send a strong glutamatergic projection, the mossy fibre tract, toward the hippocampal CA3 field, where it excites pyramidal cells and neighbouring inhibitory interneurons. Despite their excitatory nature, granule cells contain small amounts of GAD (glutamate decarboxylase), the main synthetic enzyme for the inhibitory transmitter GABA. Chronic temporal lobe epilepsy results in transient upregulation of GAD and GABA in granule cells, giving rise to the speculation that following overexcitation, mossy fibres exert an inhibitory effect by release of GABA. We therefore stimulated the DG and recorded synaptic potentials from CA3 pyramidal cells in brain slices from kindled and control rats. In both preparations, DG stimulation caused excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences. These potentials could be completely blocked by glutamate receptor antagonists in control rats, while in the kindled rats, a bicuculline-sensitive fast IPSP remained, with an onset latency similar to that of the control EPSP. Interestingly, this IPSP disappeared 1 month after the last seizure. When synaptic responses were evoked by high-frequency stimulation, EPSPs in normal rats readily summate to evoke action potentials. In slices from kindled rats, a summation of IPSPs overrides that of the EPSPs and reduces the probability of evoking action potentials. Our data show for the first time that kindling induces functionally relevant activity-dependent expression of fast inhibition onto pyramidal cells, coming from the DG, that can limit CA3 excitation in a frequency-dependent manner.

In vitro ictogenesis and parahippocampal networks in a rodent model of temporal lobe epilepsy

“…We further substantiated these findings by recently showing that in chronically epileptic rats the expression of FosB/ΔFosB is decreased in the CA3 subfield, which also appeared to be hypoactive in response to mossy fiber but not to local stimulation (Biagini et al, 2005). In addition, it has been reported that the excitatory drive provided by granule cells of the dentate gyrus onto the CA3 area is functionally impaired in kindled animals due to the emergence of activity-dependent fast inhibition (Gutiérrez and Heinemann, 2001). …”

GABAergic Signaling at Mossy Fiber Synapses in Neonatal Rat Hippocampus

“…Although in previous studies from young and epileptic animals (Gutierrez and Heinemann, 2001;Walker et al, 2001;Gutierrez et al, 2003) GABA was shown to be released together with glutamate, the present report clearly demonstrates that, during the first postnatal week, the principal neurotransmitter released from MF into principal cells and inter- neurons is GABA. Although we cannot exclude the possibility that glutamate is coreleased with GABA, the lack of NMDAmediated synaptic responses at ϩ40 mV indicates that, if released, the amount of glutamate is insufficient to activate highaffinity NMDA receptors.…”

“…Thus, in the hippocampus of epileptic animals (Gutierrez and Heinemann, 2001;Romo-Parra et al, 2003), monosynaptic GABAergic IPSPs occur in principal cells in response to dentate gyrus stimulation. Seizures are associated with a transient upregulation of the GABAergic markers GAD65 and GAD67 (Schwarzer and Sperk, 1995;Sloviter et al, 1996), as well as the mRNA for the vesicular GABA transporter (VGAT) (Lamas et al, 2001).…”

Programmed and Induced Phenotype of the Hippocampal Granule Cells

“…The localization of BDNF mRNA and its translation to protein in dendrites can be an effective means to activate neighboring GCs (Tongiorgi et al, 2004), and its anterograde transport would effectively provide a mechanism to release BDNF in terminals to produce additional neurotransmitter release by an increase in excitability (Altar and DiStefano, 1998;Elmer et al, 1998;Binder et al, 1999). Thus, sustained depolarization and release of BDNF (Thoenen, 1995) by excessive excitatory input onto GCs can underlie the expression of their GABAergic phenotype as an adaptive response (Gutiérrez and Heinemann, 2001;Gutiérrez, 2002Gutiérrez, , 2003. Indeed, BDNF promotes calcium influx (Berninger et al, 1993) and, as we previously showed, neurotransmitter release (Berzaghi et al, 1995;Thoenen, 1995).…”

“…Under these conditions, the activation of GCs provokes, in addition to monosynaptic glutamatergic responses, monosynaptic GABAergic responses on pyramidal cells and interneurons of hippocampal area CA3. Moreover, the emergence of GABAergic transmission depends on protein synthesis (Gutiérrez, 2000(Gutiérrez, , 2002Gutiérrez and Heinemann, 2001;RomoParra et al, 2003).…”