Regional and developmental profile of modulation of hippocampal synaptic transmission and LTP by AP4-sensitive mGluRs in vivo

Abstract

L-AP4 is an agonist at the presynaptic metabotropic receptor subtypes mGluR4, mGluR6 and mGluR7. In vitro, L-AP4 has been shown to reduce glutamate release and thereby suppress hippocampal excitatory transmission. Little data is available with regard to the actions of this compound in vivo. This study examined the effects of L-AP4 injected i.c.v. in the hippocampus of freely-moving rats on synaptic transmission and long-term potentiation (LTP). Two age groups were employed: 8-week-old and 12-week-old. Administration of L-AP4, 80 mM/5 microliters, reduced evoked baseline responses in the dentate gyrus (DG) and CA1 of 8-week-old rats when compared with controls. This effect was blocked by MCPG. L-AP4, 40 mM/5 microliters, also reduced baseline in DG but not CA1. L-AP4 (20, 40 or 80 mM/5 microliters) had no effect on baseline in either DG or CA1 of 12-week-old animals. However, injection of L-AP4 (80 mM/5 microliters) significantly reduced the amplitude of LTP induced by tetanization in CA1 and DG. This effect was blocked by MCPG (200 mM/5 microliters). LTP reduction, tested in 12-week-old animals, also occurred with an L-AP4 concentration of 40 mM/5 microliters in CA1 but not in DG. These data indicate that L-AP4 inhibits LTP in vivo with a variation in sensitivity to the drug occurring between regions. It is suggested that the response in CA1 is produced by mGluR7, and in DG by presynaptic mGluR4 present on perforant path neurons. These results offer in vivo physiological evidence for a variation in functional response and in developmental regulation of these subtypes, dependent on the region of the hippocampus where they are located.