A full list of affiliations appears at the end of the paper. 'N euroglia' or 'glia' are collective terms describing cells of neuroepithelial (oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, ependymal cells), neural crest (peripheral glia), and myeloid (microglia) origin. Changes in neuroglia associated with diseases of the CNS have been noted, characterized, and conceptualized from the very dawn of neuroglial research. Rudolf Virchow, in a lecture to students and medical doctors in 1858, stressed that 'this very interstitial tissue [that is, neuroglia] of the brain and spinal marrow is one of the most frequent seats of morbid change... ' 1. Changes in the shape, size, or number of glial cells in various pathological contexts have been frequently described by prominent neuroanatomists 2. In particular, hypertrophy of astrocytes was recognized very early as an almost universal sign of CNS pathology: 'the protoplasmic glia elements [that is, astrocytes] are really the elements which exhibit a morbid hypertrophy in pathological conditions' 3. Neuroglial proliferation was thought to accompany CNS lesions, leading to early suggestions that proliferating glia fully replaced damaged neuronal elements 4. Thus, a historical consensus was formed that a change in 'the appearance of neuroglia serves as a delicate indicator of the action of noxious influences upon the central nervous system, ' and the concept of 'reactionary change or gliosis' was accepted 5. While the origin of 'gliosis' is unclear (glia + osis in Greek means 'glial condition or process'; in Latin the suffix-osis acquired the additional meaning of 'disease'; hence 'astrogliosis'

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GABA(A) receptors can mediate both 'phasic' synaptic inhibition and a persistent 'tonic' form of signaling. We show that, in the presence of intact GABA uptake, guinea pig hippocampal interneurons, but not pyramidal cells, express a tonic GABA(A) receptor-mediated conductance. This conductance was pharmacologically distinct from spontaneous inhibitory postsynaptic currents (IPSCs). Inhibiting GABA uptake resulted in the expression of a comparable GABA(A) receptor-mediated tonic conductance in pyramidal cells. Reducing the tonic conductance in interneurons enhanced their excitability and the inhibitory drive to pyramidal cells. These results point to a role for cell type-dependent tonic inhibition in regulating cortical excitability.

Persistent activation of GABA A receptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by ␣5-subunit-containing GABA A receptors (␣5GABA A Rs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that ␣5GABA A Rs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of ␦-subunit-containing GABA A receptors predominates. In epileptic tissue, ␣5GABA A Rs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of ␣5GABA A Rs by other GABA A receptor subtypes. These results reveal multiple components of tonic GABA A receptormediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures.

Although GABA A receptors are widely distributed at inhibitory synapses on dendrites and cell bodies of neurons, they also occur in other places, in particular at synapses made on axons and in extrasynaptic membranes. This review summarises some of the evidence that presynaptic receptors modulate transmission not only at primary afferents in the spinal cord, but also at a variety of sites in the brain, including hippocampal mossy fibres. These receptors modulate transmitter release via several different mechanisms. Another form of unconventional GABA A receptor-mediated signalling is the mediation of a tonic conductance, seen in granule cells of the cerebellum and dentate gyrus and also in hippocampal interneurons. Tonic signalling appears to be mediated by extrasynaptic receptors. The adaptive significance of this form of signalling remains poorly understood.

Synapses between hippocampal interneurons are an important potential target for modulatory influences that could affect overall network behavior. We report that the selective group III metabotropic receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depresses GABAergic transmission to interneurons more than to pyramidal neurons. The L-AP4-induced depression is accompanied by changes in trial-to-trial variability and paired-pulse depression that imply a presynaptic site of action. Brief trains of stimuli in Schaffer collaterals also depress GABAergic transmission to interneurons. This depression persists when GABA(B) receptors are blocked, is enhanced by blocking glutamate uptake, and is abolished by the group III metabotropic receptor antagonist (alpha-methylserine-O-phosphate (MSOP). The results imply that GABAergic transmission among interneurons is modulated by glutamate spillover from excitatory afferent terminals.

Inhibition is a physiological process that decreases the probability of a neuron generating an action potential. The two main mechanisms that have been proposed for inhibition are hyperpolarization and shunting. Shunting results from increased membrane conductance, and it reduces the neuron-firing probability. Here we show that ambient GABA, the main inhibitory neurotransmitter in the brain, can excite adult hippocampal interneurons. In these cells, the GABAA current reversal potential is depolarizing, making baseline tonic GABAA conductance excitatory. Increasing the tonic conductance enhances shunting-mediated inhibition, which eventually overpowers the excitation. Such a biphasic change in interneuron firing leads to corresponding changes in the GABAA-mediated synaptic signalling. The described phenomenon suggests that the excitatory or inhibitory actions of the current are set not only by the reversal potential, but also by the conductance.

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