Dissections of somatostatin interneurons and endocannabinoid mobilization dysfunctions associated with contextual fear memory deficits in mouse models of Alzheimer's disease원문보기
Amyloid beta (Aβ) in Alzheimer’s disease (AD) impairs neural correlates of hippocampal memory such as hippocampal theta oscillations and synaptic plasticity. These neural correlates of memory are modulated by GABAergic inhibition from hippocampal somatostatin (SST) interneurons or endocannabinoid (e...
Amyloid beta (Aβ) in Alzheimer’s disease (AD) impairs neural correlates of hippocampal memory such as hippocampal theta oscillations and synaptic plasticity. These neural correlates of memory are modulated by GABAergic inhibition from hippocampal somatostatin (SST) interneurons or endocannabinoid (eCB) system but how such GABAergic inhibitions are affected by AD’s amyloidosis during memory processes are yet unclear. Thus, this thesis aimed to investigate the changes of SST interneurons or eCB system and how these changes impact neural correlates of contextual fear memory (CFM) in in vitro and in vivo models of AD through fiber photometry, electrophysiology, and optogenetics as well as molecular analysis. After contextual fear conditioning (CFC) task, Ca2+ response and firing rate of SST interneurons decreased in 5XFAD/SST-Cre mice, which is novel transgenic mice for investigation of SST interneurons, and this alteration correlated with impairment of theta oscillations and CFM recall. Additionally, optogenetic suppression of SST interneurons showed similar impairment of theta oscillation and CFM in control SST-Cre mice while optogenetic activation of SST interneurons rescued impairment of theta oscillation and CFM in 5XFAD/SST-Cre mice. Further, through ex vivo electrophysiology, it was found that decreased SST interneuron activity was derived from dysfunction of CA1 pyramidal cell (PC)-to-SST interneuron synapses in 5XFAD/SST-Cre mice. Moreover, in in vitro model of AD, optogenetic activation of SST interneuron fully restored spike-timing-dependent potentiation (tLTP) at hippocampal CA3-CA1 synapse that was impaired by Aβ by reinstating SST interneuron-mediated disinhibition into CA1 PC. Since GABAergic disinhibition to CA1 PC is thought to important for hippocampal tLTP, eCB-mediated disinhibition was also explored to find molecular mechanisms in CFM deficits in AD. A mediator of eCB signaling pathway, PLCβ1 protein, was a decrease in 5XFAD mice, which correlated to the impairments of eCB-mediated disinhibition to CA1 PC, tLTP, and CFM. However, these impairments were restored by pharmacological activation of PLCβ1 in 5XFAD mice. Together, this thesis demonstrates how amyloidosis induces dysfunctions of SST interneurons and eCB-mediated GABAergic inhibition to impair neural correlates of hippocampal memory in a mouse model of AD. These results will not only provide new insights in understanding memory processing in healthy brains but also provide new therapeutic targets for AD in the future.
Amyloid beta (Aβ) in Alzheimer’s disease (AD) impairs neural correlates of hippocampal memory such as hippocampal theta oscillations and synaptic plasticity. These neural correlates of memory are modulated by GABAergic inhibition from hippocampal somatostatin (SST) interneurons or endocannabinoid (eCB) system but how such GABAergic inhibitions are affected by AD’s amyloidosis during memory processes are yet unclear. Thus, this thesis aimed to investigate the changes of SST interneurons or eCB system and how these changes impact neural correlates of contextual fear memory (CFM) in in vitro and in vivo models of AD through fiber photometry, electrophysiology, and optogenetics as well as molecular analysis. After contextual fear conditioning (CFC) task, Ca2+ response and firing rate of SST interneurons decreased in 5XFAD/SST-Cre mice, which is novel transgenic mice for investigation of SST interneurons, and this alteration correlated with impairment of theta oscillations and CFM recall. Additionally, optogenetic suppression of SST interneurons showed similar impairment of theta oscillation and CFM in control SST-Cre mice while optogenetic activation of SST interneurons rescued impairment of theta oscillation and CFM in 5XFAD/SST-Cre mice. Further, through ex vivo electrophysiology, it was found that decreased SST interneuron activity was derived from dysfunction of CA1 pyramidal cell (PC)-to-SST interneuron synapses in 5XFAD/SST-Cre mice. Moreover, in in vitro model of AD, optogenetic activation of SST interneuron fully restored spike-timing-dependent potentiation (tLTP) at hippocampal CA3-CA1 synapse that was impaired by Aβ by reinstating SST interneuron-mediated disinhibition into CA1 PC. Since GABAergic disinhibition to CA1 PC is thought to important for hippocampal tLTP, eCB-mediated disinhibition was also explored to find molecular mechanisms in CFM deficits in AD. A mediator of eCB signaling pathway, PLCβ1 protein, was a decrease in 5XFAD mice, which correlated to the impairments of eCB-mediated disinhibition to CA1 PC, tLTP, and CFM. However, these impairments were restored by pharmacological activation of PLCβ1 in 5XFAD mice. Together, this thesis demonstrates how amyloidosis induces dysfunctions of SST interneurons and eCB-mediated GABAergic inhibition to impair neural correlates of hippocampal memory in a mouse model of AD. These results will not only provide new insights in understanding memory processing in healthy brains but also provide new therapeutic targets for AD in the future.
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