Synaptic strength at the temporoammonic input to the hippocampal CA1 region in vivo is regulated by NMDA receptors, metabotropic glutamate receptors and voltage-gated calcium channels.

The hippocampal CA1 region receives cortical information via two main inputs: directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway. Although synaptic plasticity has been reported at the pp-CA1 synapse of freely behaving animals, the mechanisms underlying this phenomenon have not been investigated. Here, we explored whether long-term potentiation (LTP) at the pp-CA1 synapse in freely behaving rats requires activation of N-methyl-d-aspartate receptors (NMDAR) and L-type voltage-gated calcium channels (VGCCs). As group II metabotropic glutamate (mGlu) receptors are densely localized on presynaptic terminals of the perforant path, and are important for certain forms of hippocampal synaptic plasticity, we also explored whether group II mGlu receptors affect LTP at the pp-CA1 synapse and/or regulate basal synaptic transmission at this synapse in vivo. In adult male rats, high-frequency stimulation (200Hz) given as 3, or 10 trains, resulted in robust LTP that lasted for at least 4h in pp-CA1 or pp-dentate gyrus (DG) synapses, respectively. Pre-treatment with the NMDAR antagonist D-(-)-2-amino-5-phosphopentanoic acid (D-AP5) partially inhibited LTP at pp-CA1, and completely prevented LTP at pp-DG synapses. Combined antagonism of NMDAR using D-AP5 and the VGCC inhibitor, (-)-methoxyverapamil hydrochloride elicited a further inhibition of the LTP response at pp-CA1 synapses. Whereas activation of group II mGlu receptors using (1R,2R)-3-((1S)-1-amino-2-hydroxy-2-oxoethyl) cyclopropane-1,2-dicarboxylic acid (DCG-IV) dose-dependently reduced basal synaptic transmission elicited by test-pulse stimulation, DCG-IV did not affect LTP in a dose that inhibited LTP at pp-DG synapses in vivo. These data indicate that LTP at the pp-CA1 synapse of freely behaving animals is dually dependent on NMDAR and VGCCs, whereby group II mGlu receptor activation affect basal synaptic tonus, but not LTP. The lower frequency-dependency of NMDA-VGCC LTP at pp-CA1 synapses compared to pp-DG synapses may comprise a mechanism to prioritize information processing at this synapse.