Novel roles of the endocannabinoid system in modulating synaptic plasticity
Learning and memory formation are invaluable processes in human life; however, the cellular mechanisms that control these phenomena are largely unknown. Synaptic plasticity, which is the ability of the synapse between two neurons to change in strength based on activity, is believed to be a key process in the formation of memories and learning. Endocannabinoids (eCB) have recently emerged as important modulators of synaptic plasticity but their precise roles and mechanisms are not well understood and many contradictions exist in the current literature. We have investigated the roles of eCBs and their primary receptor, the CB1 receptor, in the central nervous system using electrophysiological recordings in rodent hippocampus. We find that a moderate frequency 10 Hz stimulation protocol produces long-term potentiation (LTP) that is modulated by eCBs in both mice and rats; but surprisingly, the roles played by eCBs differ greatly between species. In rats, 10 Hz LTP requires CB1 receptor activation, as it is completely abolished by the CB1 antagonists AM251 and SR141716. Unlike theta burst stimulation (TBS) induced LTP, 10 Hz LTP does not require NMDA receptor activation. However, it is prevented when both NMDA and group1 mGluR receptors are blocked. The 10 Hz LTP is also independent of GABAergic synaptic inhibition, suggesting it is a novel form of excitatory synaptic plasticity mediated by the eCB system in hippocampus. In mice, we find that CB1 has an inhibitory effect on 10 Hz induced LTP. When the receptor is genetically removed in CB1 (-/-) mice or pharmacologically blocked wild type mice, 10 Hz LTP is greatly facilitated. Similar to TBS LTP, 10 Hz LTP in mice is NMDA receptor mediated. Also, the ability to achieve successful long-term depression (LTD) is decreased in CB1 (-/-) mice; yet, the magnitude of successful LTD is not changed. Together, this data supports a role for the CB1 receptor in inhibiting the induction of LTP with moderate stimulation protocols in mice, while in rats CB1 activation is required for 10 Hz LTP. Overall, our data supports that eCBs are crucial modulators of synaptic plasticity, although the roles they play may differ among species.
CB1, endocannabinoid, hippocampus, long-term potentiation, LTP, synaptic plasticity
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