Ischaemia-induced long-term hyperexcitability in rat neocortex.

The long-term structural and functional consequences of transient forebrain ischaemia were studied with morphological, immunohistochemical and in vitro electrophysiological techniques in the primary somatosensory cortex of Wistar rats. After survival times of 10-17 months postischaemia, neocortical slices obtained from ischaemic animals were characterized by a pronounced neuronal hyperexcitability in comparison with untreated age-matched controls. Extra- and intracellular recordings in supragranular layers revealed all-or-none long-latency recurrent responses to orthodromic synaptic stimulation of the afferent pathway. These responses were characterized by durations up to 1.7 s, by multiple components and by repetitive synaptic burst discharges. The reversible blockade of this late activity by DL-amino-phosphonovaleric acid (APV) suggested that this activity was mediated by N-methyl-D-aspartate (NMDA) receptors. The peak conductance of inhibitory postsynaptic potentials was significantly smaller in neurons recorded in neocortical slices obtained from ischaemic animals than those from the controls. However, the average number of parvalbumin (PV)-labelled neurons per mm3, indicative of a subpopulation of GABAergic interneurons, and the average number and length of dendritic processes arising from PV-containing cells was not significantly different between ischaemic and control cortex. The prominent dysfunction of the inhibitory system in ischaemic animals occurred without obvious structural alterations in PV-labelled cells, indicating that this subpopulation of GABAergic interneurons is not principally affected by ischaemia. Our data suggest a long-term down-regulation of inhibitory function and a concurrent NMDA receptor-mediated hyperexcitability in ischaemic neocortex. These alterations may result from structural and/or functional properties of inhibitory non-PV-positive neurons or permanent functional modifications on the subcellular molecular level, i.e. alterations in the phosphorylation status of GABA and/or NMDA receptors. The net result of these long-term changes is an imbalance between the excitatory and inhibitory systems in the ischaemic cortex with the subsequent expression and manifestation of intracortical hyperexcitability.

Astrocytic GABA receptors.

GABA receptors are distributed widely throughout the central nervous system on a variety of cell types. It has become increasingly clear that astrocytes, both in cell culture and tissue slices, express abundant GABAA receptors. In astrocytes, GABA activates Cl(-)-specific channels that are modulated by barbiturates and benzodiazepines; however, the neuronal inverse agonist methyl-4-ethyl-6, 7-dimethoxy-beta-carboline-3-carboxylate enhances the current in a subpopulation of astrocytes. The properties of astrocytic GABAA receptors, therefore, are remarkably similar to their neuronal counterparts, with only a few pharmacological exceptions. In stellate glial cells of the pituitary pars intermedia, GABA released from neuronal terminals activates postsynaptic potentials directly. The physiological significance of astrocytic GABAA-receptor activation remains unknown, but it may be involved in extracellular ion homeostasis and pH regulation. At present, there is considerably less evidence for the presence of GABAB receptors on astrocytes. The data that have emerged, however, indicate a prominent role for second-messenger regulation by this receptor.

Postsynaptic potentials mediated by GABA and dopamine evoked in stellate glial cells of the pituitary pars intermedia.

Studies have shown that many glial cells in the CNS possess receptors for neurotransmitters and that synapse-like contacts exist between glial cells and axonal terminals. Although synapse-like contacts are present between the glial cells (stellate cells) of the pituitary pars intermedia and the axons from the arcuate nucleus, it is not known whether these cells are under synaptic control. The objective of the present study was to determine whether transmitter-mediated postsynaptic potentials occurred in the stellate cells of the rat pituitary pars intermedia. Whole pituitaries were maintained in vitro, and a stimulating electrode was placed on the stalk to activate afferent fibers. Intracellular recordings were obtained with sharp microelectrodes. Stellate cells showed electrophysiological characteristics of macroglia including a resting potential more negative than -65 mV, low input resistance (< 50 M omega), and no detectable voltage-activated conductances. Single-pulse afferent nerve (stalk) stimulation evoked a [Ca2+]o-dependent postsynaptic response in the stellate cells consisting of a depolarization (< 500 msec) and a long-lasting hyperpolarization (45-75 sec). The depolarization was mimicked by GABA application and blocked by the GABAA antagonist bicuculline (100 microM). Repetitive stimulation of the stalk increased the amplitude and prolonged the GABA-mediated depolarization, during which a decrease in input resistance was observed. The hyperpolarization was mimicked by dopamine and blocked by the D2 antagonists sulpiride (2 microM) and domperidone (10 microM). Nipecotic acid (100 microM; an inhibitor of GABA uptake) or GBR 12909 (15 microM; an inhibitor of dopamine uptake) had minimal effects on the synaptic responses.(ABSTRACT TRUNCATED AT 250 WORDS)