Mechanisms of Long-Lasting Depression of Synaptic Transmission in the CA1 Region of the Rat Hippocampus

Low-frequency tetanic stimulation (2 sec^-1, 5 min) of Schaffer collaterals (SchC) in superfused slices of the dorsal hippocampus of 12- to 15-day-old rats was demonstrated to evoke homosynaptic long-lasting depression (LLD) of synaptic transmission. The same procedure applied to hippocampal slices of mature (8-week-old or older) rats failed to elicit LLD. Low-frequency tetanic stimulation of the alveus in hippocampal slices, applied under conditions of intensified NMDA glutamate receptor functioning, led to the development of heterosynaptic LLD of synaptic transmission in the SchC–dendrites of the CA1 pyramidal neurons system. Both LLD cases were either absent or weakened when hippocampal slices were treated with a competitive blocker of the NMDA glutamate receptors, D-2-amino-5-phosphonovalerate (50 M). Morphine hydrochloride (10 M), as well as inhibitors of calmodulin and calcineurin (trifluoroperasine and cyclosporin A in concentrations of 1 and 50 M, respectively), interfered with induction of LLD or decreased its intensity. A blocker of the L-type voltage-dependent Ca²⁺ channels, nifedipine (10 M), did not influence homosynaptic LLD, but decreased heterosynaptic depression. Both types of depression of synaptic transmission were facilitated upon application of substances possessing a nootropic activity, 1 mM pyracetam or 5 M carbacetam. A blocker of NO synthase, N-nitro-L-arginine (10 M) did not alter either type of LLD. When hippocampal slices were influenced with a blocker of the A1 adenosine receptors, 1,3-dipropyl-8-phenylxanthine (1 M, 15 min), both LLD forms were intensified, and the development of homosynaptic LLD of synaptic transmission became possible in hippocampal slices of mature rats. When hippocampal slices were treated with an inhibitor of protein kinase C, polymyxin B (50 M, 15 min), intensification of LLD and, in particular, the development of homosynaptic LLD of synaptic transmission were observed. When an inhibitor of phospholipase A2, mepacrine (25 M, 15 min), was applied to hippocampal slices, both forms of LLD of synaptic transmission were significantly suppressed.