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P3‐169: OPTOGENETIC QUANTAL ANALYSIS OF BASAL FOREBRAIN SYNAPTIC TRANSMISSION WITH PHARMACOLOGICAL TESTING OF SYNAPTIC ACTIVITY WITH GLUTAMATE AND CALCIUM MODULATORS
Author(s) -
Montgomery Karienn S.,
Murchison David,
Griffith William H.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.1527
Subject(s) - neuroscience , inhibitory postsynaptic potential , optogenetics , excitatory postsynaptic potential , neurotransmission , postsynaptic potential , synaptic plasticity , basal forebrain , gabaergic , biology , cholinergic , psychology , biochemistry , receptor
mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer’s Disease (AD), implicating the two isoforms of mammalian phosphatidyl choline cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies. Methods: Synaptosomal Western blot analysis on post-mortem human hippocampus, temporal cortex and frontal cortex of AD patient brains/age-matched controls and 3XTg-AD mice hippocampus [mouse model with overexpression of human amyloid precursor protein (APP), presenilin1 gene (PSEN1) and microtubule-associated protein tau (MAPT) causing neuropathology progressing comparable to that in human AD patients] were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation (LTP) of PLD1-dependent changes were studied using pharmacological approaches in ex vivo slice preparations from wildtype and transgenic mouse models. Lastly, PLD1-dependent changes in novel object recognition (NOR) memory were assessed following PLD1 inhibition. Results:We observed elevated synaptosomal PLD1 in hippocampus/temporal cortex from post-mortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increase in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric Ab (oAb) or toxic oligomeric tau species (otau) on high-frequency stimulation (HFS) LTP and NOR deficits in wildtype mice. Lastly, PLD1 inhibition blocked LTP deficits normally observed in aging 3XTg-ADmice.Conclusions:Using human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies towards future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.