A role for synaptic and network plasticity in controlling epileptiform activity in CA1 in the kainic acid‐lesioned rat hippocampus in vitro.

Abstract

1. Stimulation of the surviving afferents in the stratum radiatum of the CAl area in kainic acid-lesioned hippocampal slices produced graded epileptiform activity, part of which (> 20 %) involved the activation of N-methyl-D-aspartate (NMDA) receptors. There was also a failure of synaptic inhibition in this region. In this preparation, we have tested the effects of low-frequency stimulation (LFS; 1 Hz for 15 min) on synaptic responses and epileptiform activity.2. LFS resulted in long-term depression (LTD) of excitatory synaptic potentials (EPSPs), longterm decrease of population spike amplitudes (PSAs) and EPSP-spike (E-S) potentiation. Evoked epileptiform activity was reduced but neurons had a higher probability of discharge. LTD could be reversed by subsequent tetanic stimulation whereas E-S dissociation remained unchanged. Synaptic and network responses could be saturated towards either potentiation or depression. However, E-S potentiation was maximal following the first conditioning stimulus. 3. NMDA receptor-mediated responses were pharmacologically isolated. LFS resulted in LTD of synaptic responses, long-term decrease of PSAs and E-S depression. These depressions could not be reversed by subsequent tetanic stimulation. a-Amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) and NMDA receptor-mediated responses were then measured in isolation before and following conditioning stimuli. LFS was shown to simultaneously produce LTD of AMPA and NMDA receptor-mediated responses. E-S potentiation of the AMPA component and E-S depression of the NMDA component occurred coincidentally. 4. LTD of AMPA and NMDA receptor-mediated responses were shown to be NMDA dependent. In contrast, E-S potentiation and depression occurred even when NMDA receptors were pharmacologically blocked. 5. These findings indicate that synaptic responses could be modified bidirectionally in the CAI area of kainic acid-lesioned rat hippocampus in an NMDA receptor-dependent manner.However, E-S dissociations were independent of the activation of NMDA receptors, hinting at mechanisms different from those of synaptic LTD. We suggest that changes in E-S coupling were caused by a modification of the firing threshold of the CAl pyramidal neurons.Furthermore, the firing mechanisms controlling NMDA and AMPA receptor-mediated network activity appeared to be different. The possible use of LFS applied to the hippocampus as a clinical intervention to suppress epileptiform activity is discussed.The understanding of the plasticity of synaptic and network common mechanisms through the activation of N-methylresponses in the hippocampus may provide some insight D-aspartate (NMDA) receptors. As a consequence, the into mechanisms that can be used to control epileptiform manipulation of one phenomenon may also strongly affect activity and the generation of epileptiform discharges. the other. On the one hand, if long-term potentiation (LTP) However, epileptiform activity and synaptic plasticity share of synaptic responses is induced, it is likely that the

Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

“…Interestingly, our data demonstrate that epilepsy causes loss of mGluR LTD, but does not affect NMDA-dependent synaptic depression in the CA1 region, similar to the intact NMDAdependent LTD in the CA1 region after hippocampal lesions induced by kainic acid injection (Bernard and Wheal, 1996). These findings argue for a differential impairment of NMDAdependent and -independent forms of LTD in the CA1 region.…”

“…These findings argue for a differential impairment of NMDAdependent and -independent forms of LTD in the CA1 region. It has been suggested that the preservation of such forms of depression might be of use to decrease excitability in the epileptic hippocampus using low-frequency stimulation (Bernard and Wheal, 1996). Although we did not address this issue, it should be noted that the downregulation of mGluR5 may also have effects on NMDA-dependent forms of LTP, because mGluR5 has been implicated in NMDA-dependent LTP in the CA1 region (Lu et al, 1997;Francesconi et al, 2004).…”

CA3-Driven Hippocampal-Entorhinal Loop Controls Rather than SustainsIn VitroLimbic Seizures

“…Therefore, cell and/or synapse loss between the CA3 and CA1 regions of the hippocampus may be sufficient to prevent the hippocampal-driven control of spontaneous recurrent seizures of entorhinal origin. This view is in line with the ability of low-frequency stimulation of surviving CA1 afferents (1 Hz for 15 min) to reduce epileptiform activity in the kainic acid lesioned rat hippocampus (Bernard and Wheal, 1996). Hence, low frequency (0.25-1.5 Hz) stimulation of the hippocampal outputs in patients with temporal lobe epilepsy may represent the basis for a new direction in clinical epilepsy research.…”

Operative GABAergic inhibition in hippocampal CA1 pyramidal neurons in experimental epilepsy

“…Rats were perfused with modified artificial cerebrospinal fluid and 400 m-thick slices were prepared with a Leica (Deerfield, IL) VT 1000E tissue slicer as previously described (14). Artificial cerebrospinal fluid contained (in mM) 124 NaCl, (17). Bipolar twisted NiCr wire stimulation electrodes (trimel insulated apart from 50 m at the tip) were placed in the stratum radiatum of the CA1 area close to stratum pyramidale and 0.5 mm from the recording electrode.…”