Activation of PLCβ1 enhances endocannabinoid mobilization to restore hippocampal spike-timing-dependent potentiation and contextual fear memory impaired by Alzheimer’s amyloidosis

Abstract

Background Accumulation 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. Methods We 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. Results We 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. Conclusion We 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.

ScISOr-ATAC reveals convergent and divergent splicing and chromatin specificities between matched cell types across cortical regions, evolution, and in Alzheimer’s Disease

“…Whereas excitatory neurons only show a 9% increase in exon inclusion in controls, a 40% increase occurs in oligodendrocytes ( Fig 5k ). Interestingly, knockdown has been shown to relieve amyloid-beta induced calcium overload 64 , while activation restores AD-impaired hippocampal potentiation 65 . A further example, which illustrates cell-subtype specific splicing dysregulation is found in the Vacuolar Protein Sorting-Associated Protein 8 (VPS8) gene.…”

Decoding the underlying neural activity of neurodegeneration in Alzheimer’s Disease

“…Moreover, PLCγ1 gene expression was enriched in AD patients [41], and PLC-γ protein level was significantly higher in the cytosolic fraction of AD cortical tissue than in control brains; however, its specific activity is compromised in AD brains [42], suggesting that its inactivation might be related to the pathophysiology of AD. Also, restoration of PLCβ1 activation ameliorated hippocampal longterm potentiation impaired by Aβ plaque accumulation [43], but further elevation by Aβ facilitates calcium overload (Park et al, 2022). Therefore, other genes encoding primary phospholipase C proteins-with emphasis on Plcb4-should be investigated as potential targets for protecting neurons against excitotoxicity in AD.…”