PHARMACOLOGICAL CHARACTERIZATION OF IONOTROPIC EXCITATORY AMINO-ACID RECEPTORS IN YOUNG AND AGED RAT BASAL FOREBRAIN

Ionotropic glutamate receptors were characterized in acutely dissociat ed medial septum/nucleus of diagonal band neurons from one-to four-mon th-and 24-26-month-old male Fischer 344 rats. Whole-cell patch-clamp r ecordings were used to study glutamate, ha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate, kainate and N-methyl-D-aspartate-induced currents . Pharmacological properties of these ionotropic receptors were studie d across different age groups by comparing concentration response curv es and EC50 for agonist-induced currents, as well as dissociation cons tants (K-b) for competitive receptor antagonists. Our results suggest that non-N-methyl-D-aspartate receptors on medial septum/ nucleus of d iagonal band neurons were predominantly of the pha-amino-3-hydroxy-5-m ethyl-4-isoxazolepropionate type and display biophysical and pharmacol ogical properties similar to other central neurons. However, peak o-3- hydroxy-5-methyl-4-isoxazolepropionate-induced currents were enhanced in aged (35.0 +/- 4.4 pA/pF) compared to young cells (16.2 +/- 1.7 pA/ pF, P < 0.005), and the EC50 shifted to the right (4.4 +/- 0.6 in youn g compared to 8.8 +/- 1.3 mu M in aged, P < 0.05). The K-b for 6,7-din itroquinoxaline-2,3-dione inhibition of pha-amino-3-hydroxy-5-methyl-4 -isoxazolepropionate induced currents likewise shifted to the right (0 .16 +/- 0.02 in young and 0.29 +/- 0.04 mu M in aged, P < 0.05) sugges ting an age-related decrease in affinity for pha-amino-3-hydroxy-5-met hyl-4-isoxazolepropionate receptors. N-Methyl-D-aspartate-induced curr ents were generated in standard physiological solutions with the addit ion of 1 mu M glycine and the removal of Mg2+. The N-methyl-D-aspartat e responses were predictably modulated by magnesium and glycine, and w ere antagonized by the competitive antagonist 2-amino-5-phosphonovaler ic acid. No age-related change in N-methyl-D-aspartate maximum, EC50,m agnesium sensitivity, glycine sensitivity or K-b for 2-amino-5-phospho novaleric acid was observed. Overall, our results suggest that ionotro pic glutamate receptors in the medial septum/nucleus of diagonal band have a similar pharmacological profile compared to glutamate receptors in other brain regions. More importantly, these data suggest that whi le medial septum/nucleus of diagonal band cells maintain M-methyl-D-as partate receptors during ageing, a significant increase in current den sity and decrease in receptor affinity for pha-amino-3-hydroxy-5-methy l-4-isoxazolepropionate receptors, during this same time period, may p rovide a mechanism for age-related changes in neuronal plasticity and excitotoxicity in the basal forebrain. (C) 1997 IBRO. Published by Els evier Science Ltd.