LONG-TERM CHANGES OF IONOTROPIC GLUTAMATE AND GABA RECEPTORS AFTER UNILATERAL PERMANENT FOCAL CEREBRAL-ISCHEMIA IN THE MOUSE-BRAIN

Long-term hyperexcitability was found after unilateral, permanent midd le cerebral artery occlusion in exofocal neocortical areas of the adul t mouse [Mittmann et al. (1998) Neuroscience 85, 15-27]. The aim of th e present study was to lest the hypothesis in an identical paradigm of ischemia, whether alterations in the densities of both excitatory and inhibitory amino acid receptors may underlie these pathophysiological changes. Alterations in densities of [H-3]dizocilpine, lpha-amino-3-h ydroxy-5-methyl-4-isoxazolepropionic acid, [H-3]kainate and [H-3]musci mol binding sites were demonstrated with quantitative in vitro recepto r autoradiography. All binding sites were severely reduced in the core of the ischemic lesion. A completely different reaction was found in the exofocal, histologically inconspicous parts of the somatosensory c ortex and the more remote neocortical areas of both hemispheres. The [ H-3]muscimol binding sites were significantly reduced four weeks after ischemia in the motor cortex, hindlimb representation area and exofoc al parts of the primary and secondary somatosensory cortices of both h emispheres. The focus of the reduction in [H-3]muscimol binding sites was found in lower layer V and upper layer VI. Contrastingly, the dens ities of [H-3]dizocilpine binding sites were found to be increased in these areas, whereas those of lpha-amino-3-hydroxy-5-methyl-4-isoxazol epropionic acid and [H-3]kainate binding sites did not show significan t changes. The [H-3]dizocilpine binding site density increased predomi nantly in layers III and IV. All binding sites were also reduced in th e retrogradely reacting, gliotic part of the ipsilateral ventroposteri or thalamic nucleus, whereas the lpha-amino-3-hydroxy-5-methyl-4-isoxa zolepropionic acid binding sites were increased in the surround of the ipsilateral nucleus and no changes in binding sites were seen in the whole contralateral nucleus. We conclude that permanent local ischemia leads to a long-term and widespread impairment of the normal balance between binding sites of excitatory and inhibitory neurotransmitter re ceptors in neocortical areas far away from the focus of the post-ische mic tissue damage. The imbalance comprizes an up-regulation of the [3H ]dizocilpine binding sites in the ion channels of N-methyl-D-aspartate receptors and a down-regulation of [H-3]muscimol binding sites of the GABA, receptors in the ipsi-and contralateral neocortex. These change s at the receptor level explain the previously observed hyperexcitabil ity with the appearance of epileptiform field potentials and the long duration of excitatory postsynaptic potentials four weeks after ischem ia. (C) 1998 IBRO. Published by Elsevier Science Ltd.