Activation of PLC beta 1 enhances endocannabinoid mobilization to restore hippocampal spike-timing-dependent potentiation and contextual fear memory impaired by Alzheimer's amyloidosis

초록

Background Accumulation of amyloid beta oligomers (A beta O) in Alzheimer's disease (AD) impairs hippocampal long-term potentiation (LTP), leading to memory deficits. Thus, identifying the molecular targets of A beta O involved in LTP inhibition is critical for developing therapeutics for AD. Endocannabinoid (eCB) synthesis and release, a process collectively called eCB mobilization by hippocampal CA1 pyramidal cells, is known to facilitate LTP induction. eCB can be mobilized either by postsynaptic depolarization in an intracellular Ca2+ concentration ([Ca2+](i))-dependent pathway or by group 1 metabotropic glutamate receptor (mGluR) activation in a phospholipase C beta (PLC beta)-dependent pathway. Moreover, group 1 mGluR activation during postsynaptic depolarization, which is likely to occur in vivo during memory processing, can cause synergistic enhancement of eCB (S-eCB) mobilization in a PLC beta-dependent pathway. Although A beta O has been shown to disrupt [Ca2+](i)-dependent eCB mobilization, the effect of A beta O on PLC beta-dependent S-eCB mobilization and its association with LTP and hippocampus-dependent memory impairments in AD is unknown. Methods We used in vitro whole-cell patch-clamp recordings and western blot analyses to investigate the effect of A beta O on PLC beta protein levels, PLC beta-dependent S-eCB mobilization, and spike-timing-dependent potentiation (tLTP) in A beta O-treated rat hippocampal slices in vitro. In addition, we assessed the relationship between PLC beta protein levels and hippocampus-dependent memory impairment by performing a contextual fear memory task in vivo in the 5XFAD mouse model of AD. Results We found that A beta O treatment in rat hippocampal slices in vitro decreased hippocampal PLC beta 1 protein levels and disrupted S-eCB mobilization, as measured by western blot analysis and in vitro whole-cell patch-clamp recordings. This consequently led to the impairment of NMDA receptor (NMDAR)-mediated tLTP at CA3-CA1 excitatory synapses in A beta O-treated rat hippocampal slices in vitro. Application of the PLC beta activator, m-3M3FBS, in rat hippocampal slices reinstated PLC beta 1 protein levels to fully restore S-eCB mobilization and NMDAR-mediated tLTP. In addition, direct hippocampal injection of m-3M3FBS in 5XFAD mice reinstated PLC beta 1 protein levels to those observed in wild type control mice and fully restored hippocampus-dependent contextual fear memory in vivo in 5XFAD mice. Conclusion We suggest that these results might be the consequence of memory impairment in AD by disrupting S-eCB mobilization. Therefore, we propose that PLC beta-dependent S-eCB mobilization could provide a new therapeutic strategy for treating memory deficits in AD.

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