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The Journal of Neuroscience, August 15, 1999, 19(16):6795-6805
Mechanism of Cannabinoid Effects on Long-Term Potentiation and
Depression in Hippocampal CA1 Neurons
Dinah L.
Misner and
Jane M.
Sullivan
Molecular Neurobiology Laboratory, The Salk Institute, La
Jolla, California 92037
Cannabinoids, the active constituents of marijuana, are known to
impair learning and memory. Receptors for cannabinoids are highly
expressed in the hippocampus, a brain region that is believed to play
an important role in certain forms of learning and memory. To
investigate the possible contribution of cannabinoid receptor-mediated deficits in hippocampal function to the learning and memory impairments produced by marijuana, we studied the effects of cannabinoid receptor activation on two models of learning and memory, long-term potentiation (LTP) and long-term depression (LTD), in hippocampal slices. Although LTP and LTD of CA1 field potentials were blocked by cannabinoid receptor activation in the presence of Mg2+, they
could be induced after Mg2+ was removed. Similarly,
LTP and LTD of whole-cell EPSCs were unimpaired in the presence
of cannabinoid receptor agonist when the postsynaptic membrane was
depolarized during the LTP or LTD induction protocol. Cannabinoid
receptor activation also reduced EPSCs and enhanced paired-pulse
facilitation, while having no effect on the amplitude of spontaneous
miniature EPSCs. Finally, as with cannabinoid receptor activation,
inhibition of LTP by adenosine receptor activation could be overcome by
removal of Mg2+ or depolarization of the
postsynaptic membrane during tetanus. Our results indicate that
cannabinoid receptor activation does not directly inhibit the molecular
mechanisms responsible for long-term synaptic plasticity but instead
impairs LTP and LTD by reducing presynaptic neurotransmitter release to
a level below that required to depolarize the postsynaptic membrane to
relieve Mg2+ blockade of NMDA receptors.
Key words:
cannabinoids; cannabinoid receptors; hippocampus; synaptic transmission; long-term potentiation; long-term depression; learning and memory
Copyright © 1999 Society for Neuroscience 0270-6474/99/19166795-11$05.00/0
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