Changes in mIPSCs and sIPSCs After Kainate Treatment: Evidence for Loss of Inhibitory Input to Dentate Granule Cells and Possible Compensatory Responses

Abstract

Shao, Li-Rong and F. Edward Dudek. Changes in mIPSCs and sIPSCs after kainate treatment: evidence for loss of inhibitory input to dentate granule cells and possible compensatory responses. J Neurophysiol 94: 952-960, 2005. First published March 16, 2005 doi:10.1152/jn.01342.2004. How inhibition is altered after status epilepticus and the role of inhibition during epileptogenesis remain unsettled issues. The present study examined acute (4 -7 days) and chronic (Ͼ3 mo) changes of GABA A receptor-mediated inhibitory synaptic input to dentate granule cells after kainate-induced status epilepticus. Whole cell patch-clamp techniques were used to record spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in the presence of 6,7-dinitroquinoxaline-2,3-dione and DL-2-amino-5-phosphonopentanoic acid to block glutamatergic excitatory synaptic transmission. In both groups, mean sIPSC frequency of dentate granule cells from the saline-and kainate-treated rats was not significantly different. However, mIPSC frequency from the kainate-treated rats of both groups was ϳ30% lower than that of the respective saline controls. The mean amplitude of sIPSCs and mIPSCs from kainate-treated rats was not reduced in either the acute or chronic groups. The mean 10 -90% rise time of IPSCs was not altered in kainate-treated rats, but the decay time constant was slightly longer than in controls, and the charge transfer 4 -7 days after kainate treatment was significantly larger. The similar reduction of mIPSC frequency (i.e., ϳ30%) in the two groups of kainate-treated rats suggests a decreased inhibitory input to dentate granule cells (presumably due to a partial loss of inhibitory interneurons that innervate them) without recovery during epileptogenesis. The lack of effect on sIPSC frequency and the decreased mIPSC frequency in both groups suggests a possible compensatory increase in firing rate of interneurons, which may involve a hypothetical reduction of inhibitory input to the remaining interneurons.

Targeted disruption of layer 4 during development increases GABAAreceptor neurotransmission in the neocortex

“…mIPSCs are caused by the quantal release of GABA from presynaptic terminals of GABAergic interneurons in the absence of action potentials (Edwards et al 1990). The number of presynaptic terminals of interneurons and/or the postsynaptic GABA A R density on pyramidal cells determines the frequency of mIPSCs (Shao and Dudek 2005). In our study, both amplitude and frequency of mIPSCs were significantly increased in MAM-Tx animals relative to control.…”

Epileptogenesis

“…However, data regarding the degree and anatomical patterns of neuronal interconnectivity are exceptionally sparse because of the technical difficulty of establishing synaptic connectivity between neurons, and establishing this "connectome" is a central goal of the National Institutes of Health BRAIN project (Kandel et al 2013). Unmasking this normal positive feedback caused by damage to inhibitory neurons and their circuitry (Shao and Dudek 2005) could provide a means to increase the net functional positive feedback in epilepsy (Cronin et al 1992). Ultrastructural analyses of the dentate gyrus during epileptogenesis revealed more g-aminobutyric acid (GABAergic) terminals after the time of onset of spontaneous seizures, suggesting that some aspects of GABAergic synaptic transmission may not be functional (Thind et al 2010).…”

Mechanisms of physiological and epileptic HFO generation

“…This may affect inhibitory synaptic currents during HFO in the 40-100 Hz range, making them either invisible, due to a zero net current flow for those neurons operating at the equilibrium potential of the chloride currents, or extracellularly reversed due to a depolarizing action of chloride ions (Payne et al, 2003). Other pro-epileptic changes including interneuronal cell loss and disinhibition of large populations of pyramidal cells (Esclapez and Houser, 1999;Kobayashi and Buckmaster, 2003;Nadler et al, 1980;Shao and Dudek, 2005) also have an indirect impact in the nature of the extracellular signals by promoting hyperexcitability and favouring the generation of pathological large excitatory potentials (Ayala et al, 1973). Finally, local circuit reorganization and glutamatergic cell loss affecting the normal pattern of input lamination have an impact in the shape of many extracellular events, which can even change polarity Fabo et al, 2008;Lopes da Silva et al, 1982;Wadman et al, 1983).…”