Abstract
BackgroundAccumulation of amyloid beta oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal long-term potentiation (LTP), leading to memory deficits. Thus, identifying the molecular targets of AβO 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 Cβ (PLCβ)-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 PLCβ-dependent pathway. Although AβO has been shown to disrupt [Ca2+]i-dependent eCB mobilization, the effect of AβO on PLCβ-dependent S-eCB mobilization and its association with LTP and hippocampus-dependent memory impairments in AD is unknown.MethodsWe used in vitro whole-cell patch-clamp recordings and western blot analyses to investigate the effect of AβO on PLCβ protein levels, PLCβ-dependent S-eCB mobilization, and spike-timing-dependent potentiation (tLTP) in AβO-treated rat hippocampal slices in vitro. In addition, we assessed the relationship between PLCβ protein levels and hippocampus-dependent memory impairment by performing a contextual fear memory task in vivo in the 5XFAD mouse model of AD.ResultsWe found that AβO treatment in rat hippocampal slices in vitro decreased hippocampal PLCβ1 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 AβO-treated rat hippocampal slices in vitro. Application of the PLCβ activator, m-3M3FBS, in rat hippocampal slices reinstated PLCβ1 protein levels to fully restore S-eCB mobilization and NMDAR-mediated tLTP. In addition, direct hippocampal injection of m-3M3FBS in 5XFAD mice reinstated PLCβ1 protein levels to those observed in wild type control mice and fully restored hippocampus-dependent contextual fear memory in vivo in 5XFAD mice.ConclusionWe suggest that these results might be the consequence of memory impairment in AD by disrupting S-eCB mobilization. Therefore, we propose that PLCβ-dependent S-eCB mobilization could provide a new therapeutic strategy for treating memory deficits in AD.
Highlights
Accumulation of amyloid beta oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal long-term potentiation (LTP), leading to memory deficits
Among the many molecular and synaptic mechanisms involved in the induction of LTP, endocannabinoids such as 2-arachidonoylglycerol (2-AG) are known to directly control the induction of hippocampal NMDA receptor (NMDAR)-mediated LTP [14, 15]. eCB is synthesized and released from postsynaptic hippocampal Cornus Ammonis1 (CA1) pyramidal cells (PCs) through a process collectively called eCB mobilization [16]. eCB acts as a retrograde messenger by binding to the presynaptic cannabinoid type 1 receptor (CB1R) to decrease the release of presynaptic neurotransmitters [17, 18] such as gammaaminobutyric acid (GABA) [19, 20] onto CA1 Pyramidal cell (PC). eCB mobilization facilitates the induction of NMDAR-mediated LTP at hippocampal Cornus Ammonis3 (CA3)-CA1 synapses [14, 15, 21, 22], while blockade of CB1R impairs the induction of NMDAR-mediated LTP [14, 15, 22]
Aβ oligomers inhibit synergistic enhancement of eCB (S-eCB) mobilization in hippocampal CA1 pyramidal cells To investigate the effect of Amyloid beta oligomers (AβO) on phospholipase Cβ (PLCβ)-dependent eCB and S-eCB mobilization in CA1 PCs, we established a protocol that can measure S-eCB mobilization induced by a concomitant activation of group 1 metabotropic glutamate receptor (mGluR) during postsynaptic depolarization
Summary
Accumulation of amyloid beta oligomers (AβO) in Alzheimer’s disease (AD) impairs hippocampal long-term potentiation (LTP), leading to memory deficits. ECB acts as a retrograde messenger by binding to the presynaptic cannabinoid type 1 receptor (CB1R) to decrease the release of presynaptic neurotransmitters [17, 18] such as gammaaminobutyric acid (GABA) [19, 20] onto CA1 PCs. eCB mobilization facilitates the induction of NMDAR-mediated LTP at hippocampal CA3-CA1 synapses [14, 15, 21, 22], while blockade of CB1R impairs the induction of NMDAR-mediated LTP [14, 15, 22]. The stage at which the eCB mobilization process is disrupted by AβO to impair LTP is unknown
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