Inhibition in kainate-lesioned hyperexcitable hippocampi: physiologic, autoradiographic, and immunocytochemical observations

Abstract

Following kainate lesions of hippocampal subfield CA3, the remaining CA 1 pyramidal cells become hyperexcitable. This lesion is of interest because, morphologically, it resembles the damage often seen in cases of temporal lobe epilepsy; it may provide insight into the consequences of such cell loss in humans. The hyperexcitability in CA 1 is associated with a loss of both early and late IPSPs. At long postlesion latencies (2–4 months) inhibition shows partial recovery and the hyperexcitability subsides. The intent of the present work was to determine if alterations in CA 1 excitability and functional inhibition postlesion are correlated with changes in morphologic and physiologic indicators of inhibitory interneuron function or with alterations in binding sites for inhibitory transmitters. Using GAD immunocytochemistry, we found no acute or chronic lesion-induced decrease in numbers of CA 1 interneurons or in qualitative characteristics of the pericellular distribution of their terminals in CA 1 stratum pyramidale. Intracellular recordings from identified cells in CA 1 indicated that putative interneurons were viable in hyperexcitable tissue. It was further observed that “recovery” in tissue studied 2–4 months postlesion primarily involved the early IPSP; the late IPSP failed to reappear. Quantitative in vitro autoradiographic analysis of 3H-flunitrazepam--a marker for the early IPSP associated GABAA receptor complex--indicated that hyperexcitability was associated with an increase in GABAA receptor number in CA 1; receptor binding returned to normal at long postlesion latencies as the early IPSP returned and hyperexcitability subsided. Finally, hyperexcitable pyramidal cells were found to retain their responsivity to exogenously applied GABA. These data indicate that much of the cellular machinery necessary for inhibition is retained in CA 1, despite lesion-induced hyperexcitability. We suggest that the acute loss of the IPSP after kainate lesion is due to a transient disconnection between inhibitory and excitatory elements in CA 1 and/or to a loss of normal afferent drive from CA3 onto some CA 1 interneurons. We further suggest that incomplete recovery can be explained by abnormalities that occur as neuroplastic rearrangements in response to deafferentation of CA 1. The relevance of these studies to human hippocampal necrosis and to other models of focal epilepsy is discussed.

Excitatory synaptic potentials in kainic acid-denervated rat CA1 pyramidal neurons

“…Likewise, the graded bursts recorded from the lesioned slices ( Fig. 2; Franck et al, 1988) were significantly different from the structured bursts associated with acute loss of postsynaptic inhibition (Dingledine and Gjerstad, 1980;Wheal et al, 1984), suggesting that more features are present than the loss of the inhibitory drive alone. Thus, the present findings are not compatible with the loss of inhibitory drive as the sole mechanism leading to hyperexcitability, and changes in the predominant receptor mechanisms underlying the EPSP (non-NMDA and NMDA) appear to have a significant role in the hyperexcitability.…”

“…Thus, the present findings may be a phase in response to the denervation, and some degree of recovery may occur over several weeks (Cavalheiro et al, 1982), as suggested by anatomical studies of denervation and plasticity (Nadler et al, 1980a,b, Cotman andNeito-Sampedro, 1984;Phelps et al, 199 1). Though paired-pulse facilitation (as a result of failure of early pairedpulse inhibition) continued in vivo for weeks after a KA lesion (Cornish and Wheal, 1989) other groups studying the KA model have suggested an eventual partial recovery from the hyperexcitability associated with the KA lesion (Franck et al, 1988).…”

“…This powerful excitatory drive, in concert with the loss of postsynaptic inhibition (Ashwood et al, 1986;Franck et al, 1988;Cornish and Wheal, 1989;Wheal, 1989) suggests a marked switch in the overall input-output relationship for the CA1 neuron toward hyperexcitability. One might also suggest that the loss of the Schaffer collaterals removes the excitatory drive to the interneurons that are responsible for feedforward inhibition in the CA 1 area (Turner, 1990).…”

“…The study of chronic animal models of epilepsy and human brain tissue slices (Lothman and Collins, 198 1;Pumain, 198 1;Wheal, 1982, 1984;Schwartzkroin et al, 1983;Schwartzkroin and Knowles, 1984;Ashwood et al, 1986;Ashwood and Wheal, 1987;Avoli and Olivier, 1987;Mody and Heinemann, 1987;Franck et al, 1988;Nakajima et al, 199 1;Sloviter, 1991) has revealed new physiological mechanisms underlying bursting activity that were not observed in in vitro models generated by acute convulsants, such as penicillin and bicucilline, which block inhibitory processes (Dingledine and Gjerstad, 1980;Johnston and Brown, 198 1;Wheal et al, 1984). The chronic animal models and abnormal human tissue show less structured and more graded bursting activity than the acute convulsant models.…”

“…Other models of epilepsy involving the hippocampus, such as the kindling (McNamara et al, 1985;Mody and Heinemann, 1987) and excitability models (Sloviter, 1987(Sloviter, , 1991 also exhibit some of the pathological characteristics of the human condition (Schwartzkroin and Wyler, 1980), but in response to electrical stimulation rather than a structural lesion. The kainic acid (KA) model produced by intracerebroventricular (ICV) injection in the rat has been evaluated by several laboratories (Nadler et al, 1980a,b;Wheal, 1982, 1984;Ashwood et al, 1986;Franck et al, 1988;Turner and Wheal, 1988;Wheal and Turner, 1988;Cornish and Wheal, 1989;Nakajima et al, 199 1;Simpson et al, 199 1). This model has been previously shown to demonstrate many of the features found in the epileptic human cortex in vitro.…”