LONG-TERM CELLULAR DYSFUNCTION AFTER FOCAL CEREBRAL-ISCHEMIA - IN-VITRO ANALYSES

The long-term (<six months) functional consequences of permanent middl e cerebral artery occlusion were studied with in vitro extra- and intr acellular recording techniques in adult mouse neocortical slices. Afte r survival limes of one to three days, 28 days and six months, intrace llular recordings from layers II/III pyramidal cells in the vicinity o f the infarct did not reveal any statistically significant changes in the intrinsic membrane properties when compared to age-matched control animals. However, a pronounced hyperexcitability could be observed up on orthodromic synaptic stimulation in neocortical slices obtained fro m mice 25 days after induction of ischemia. Low-intensity electrical s timulation of the afferents elicited particularly in this group epilep tiform extracellular field potential responses and intracellular excit atory postsynaptic potentials. that were longer in duration as compare d to the controls. When the N-methyl-D-aspartate receptor-mediated exc itatory postsynaptic potential was pharmacologically isolated in a bat hing solution containing 0.1 mM Mg2+ and 10 mu M 6-cyano-7-nitroquinox aline-2,3-dione, the synaptic responses were longer and larger in the ischemic cortex as compared to the controls. Higher stimulus intensiti es evoked in normal medium a biphasic inhibitory postsynaptic potentia l, that contained in the 28 days post-ischemia group a prominent amino -phosphonovaleric acid-sensitive component, indicating a strong concur rent activation of a N-methyl-D-aspartate receptor-mediated excitatory postsynaptic potential. This pronounced co-activation could only be o bserved in the 25 days ischemic group, and neither after one to three days or six months post-ischemia nor in the controls. The quantitative analysis of the efficiency of stimulus-evoked inhibitory postsynaptic potentials recorded in amino-phosphono-valeric acid revealed a reduct ion of GABA-mediated inhibition in ischemic cortex. Although this redu ction in intracortical inhibition may already contribute to an augment ation of N-methyl-D-aspartate receptor-mediated excitation, our result s do also indicate that the function of N-methyl-D-aspartate receptors is transiently enhanced in the ischemic cortex. This transient hypere xcitability does not only cause cellular dysfunction in the vicinity o f the infarct, but may also contribute to neuronal damage due to excit otoxicity. (C) 1998 IBRO. Published by Elsevier Science Ltd.