Studies examining hippocampal plasticity typically utilize high frequency stimulation protocols to induce long-term potentiation (LTP). Recently, we have demonstrated an LTP-like enhancement of excitatory postsynaptic potentials in CA1 induced by alternating, single pulse stimulation of the medial septum and area CA3 (MS-H LTP) in vivo. Analyses of paired-pulse ratios (an indicator of changes in presynaptic transmitter release) show no change during the initial (0-2 h) phase of MS-H LTP, followed by a subsequent decline (2-4 h). Thus, MS-H LTP is comprised of temporally distinct mechanisms, an initial postsynaptic enhancement, followed by a delayed, presynaptic facilitation of transmitter release.

Hebb Award Abstract

Today, it is well established that neuronal plasticity can be acquired by specific patterns of brain activity, for example those that occur during acquisition and memory consolidation. Long-term potentiation (LTP), a stable long-lasting increase in synaptic strength as a result of high frequency stimulation of neurons, is a well characterized form of plasticity. A large majority of studies examining hippocampal synaptic enhancement and its modulation by extra-hippocampal systems has used typical LTP protocols that require high frequency stimulation (100 Hz) of glutamatergic afferents to induce long-lasting changes in synaptic efficacy. In contrast, low frequency stimulation protocols produce minimal or no LTP, or in fact may result in long-term depression (LTD). However, recent evidence indicates that some synapses can show long-lasting synaptic potentiation in response to low frequency (1 Hz) stimulation, very similar to LTP following high-frequency induction protocols. At present, the extent to which lower frequency inputs are effective in inducing synaptic potentiation in different forebrain systems and the contribution of neuromodulatory signals to such forms of plasticity are unknown.

Recently, we have demonstrated an LTP-like enhancement of excitatory postsynaptic potentials in CA1 induced by alternating, single pulse stimulation of the medial septum (MS) and area CA3 in urethane anesthetised rodents (MS-H LTP). The MS-CA3 alternating stimulation protocol consisted of 50 single pulse stimulations, with a 1 s interstimulus interval between MS and CA3 stimuli, repeated at 0.5 Hz. MS-H LTP was resistant to administration of antagonists of nicotinic and muscarinic receptors, but was abolished by a non-competitive NMDA receptor antagonist. Furthermore, an unusually long interstimulus interval (1 s) between consecutive septal and CA3 stimuli was required to elicit MS-H LTP. Interestingly, analyses of paired-pulse ratios (an indicator of changes in presynaptic transmitter release) showed no change during the initial (0-2 h) phase of MS-H LTP, after 1 MS-CA3 alternating stimulation episode, however, subsequently declined (2-4 h) after the second induction episode elicited 2 h after the first induction. Thus, MS-H LTP is comprised of temporally distinct mechanisms, an initial postsynaptic enhancement, followed by a delayed, presynaptic facilitation of transmitter release.

These experiments are the first to demonstrate lasting hippocampal plasticity through low frequency alternating medial septal and hippocampal stimulation in vivo. Our data reinforce recent findings that long-lasting synaptic enhancement can occur in response to low frequency activity patterns, which might closely mimic some aspects of natural neuronal firing patterns during phases of acquisition or consolidation of memory processes.