{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/379828"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/379828","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The Emergence of Network Hyperexcitability and Functional Impairment in a Mouse Model of Alzheimer’s Disease","abstract":"Amyloid β (Aβ) pathophysiology is a hallmark and early feature of Alzheimer’s disease (AD), developing many years before symptomatic onset. Preceding the formation of amyloid plaques, extracellular Aβ has been shown to induce synaptic dysfunction and hyperexcitability in the hippocampus. This thesis aimed to elucidate the emergence of hippocampal hyperexcitability and network dysfunction as a consequence of genotype-driven Aβ pathophysiology in a mouse model of AD. To this end, both acute ex vivo hippocampal slices and primary hippocampal cultures derived from humanised AppNL-G-F knock-in mice — which express familial AD mutations that increase the relative expression of pathogenic Aβ42 and increase Aβ oligomerisation — were evaluated utilising multi-electrode array (MEA) electrophysiological recordings. Ex vivo hippocampal slices, taken from 1- and 3-month-old AppNL-G-F mice, were challenged with increased [K+] in artificial cerebrospinal fluid (aCSF) superfusate to induce epileptiform-like activity. Inducible hyperexcitability was increased in AppNL-G-F mice compared to WT at 1-month but was comparable at 3-months. The relative decrease in inducible subregional hyperactivity (CA1, CA3, DG and EC) at the later time point coincided with the emergence of Aβ plaques within these same subregions. To better study the emergence of hyperexcitability in functional hippocampal networks, spontaneous activity from AppNL-G-F and WT primary hippocampal cultures, grown on MEAs, was regularly recorded over a 56 days-in-vitro culture maturation period. Early AppNL-G-F hippocampal hyperexcitability was recapitulated in this isolated culture system as evidenced by several indicative metrics, pertinently, through altered electrode- and network-level bursting dynamics. This translated to AppNL-G-F in vitro networks having increased functional connectivity but disrupted network topology and decreased efficiency. Moreover, conditioned AppNL-G-F media exchanged to WT cultures was sufficient to induce hyperexcitability, potentially implicating soluble Aβ as a mechanistic driver. Finally, to further explore excitation-inhibition balance in vitro, pharmacological intervention with a novel GABAΑ-R α1-selective nanobody, acting as a positive allosteric modulator, was shown to decrease activity in WT networks but paradoxically exacerbate burst-driven hyperexcitability in AppNL-G-F networks in a dose-dependent manner. Perturbed excitation-inhibition balance, and consequent network hyperexcitability and functional impairment occur at the earliest stage of pathogenesis in the AppNL-G-F mouse model of AD. Indeed, such early changes may ultimately contribute to pathological spread and symptomatology in AD.","abstract_html":"Amyloid β (Aβ) pathophysiology is a hallmark and early feature of Alzheimer’s disease (AD), developing many years before symptomatic onset. Preceding the formation of amyloid plaques, extracellular Aβ has been shown to induce synaptic dysfunction and hyperexcitability in the hippocampus. This thesis aimed to elucidate the emergence of hippocampal hyperexcitability and network dysfunction as a consequence of genotype-driven Aβ pathophysiology in a mouse model of AD. To this end, both acute ex vivo hippocampal slices and primary hippocampal cultures derived from humanised AppNL-G-F knock-in mice — which express familial AD mutations that increase the relative expression of pathogenic Aβ42 and increase Aβ oligomerisation — were evaluated utilising multi-electrode array (MEA) electrophysiological recordings. Ex vivo hippocampal slices, taken from 1- and 3-month-old AppNL-G-F mice, were challenged with increased [K+] in artificial cerebrospinal fluid (aCSF) superfusate to induce epileptiform-like activity. Inducible hyperexcitability was increased in AppNL-G-F mice compared to WT at 1-month but was comparable at 3-months. The relative decrease in inducible subregional hyperactivity (CA1, CA3, DG and EC) at the later time point coincided with the emergence of Aβ plaques within these same subregions. To better study the emergence of hyperexcitability in functional hippocampal networks, spontaneous activity from AppNL-G-F and WT primary hippocampal cultures, grown on MEAs, was regularly recorded over a 56 days-in-vitro culture maturation period. Early AppNL-G-F hippocampal hyperexcitability was recapitulated in this isolated culture system as evidenced by several indicative metrics, pertinently, through altered electrode- and network-level bursting dynamics. This translated to AppNL-G-F in vitro networks having increased functional connectivity but disrupted network topology and decreased efficiency. Moreover, conditioned AppNL-G-F media exchanged to WT cultures was sufficient to induce hyperexcitability, potentially implicating soluble Aβ as a mechanistic driver. Finally, to further explore excitation-inhibition balance in vitro, pharmacological intervention with a novel GABAΑ-R α1-selective nanobody, acting as a positive allosteric modulator, was shown to decrease activity in WT networks but paradoxically exacerbate burst-driven hyperexcitability in AppNL-G-F networks in a dose-dependent manner. Perturbed excitation-inhibition balance, and consequent network hyperexcitability and functional impairment occur at the earliest stage of pathogenesis in the AppNL-G-F mouse model of AD. 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The relative decrease in inducible subregional hyperactivity (CA1, CA3, DG and EC) at the later time point coincided with the emergence of Aβ plaques within these same subregions. To better study the emergence of hyperexcitability in functional hippocampal networks, spontaneous activity from AppNL-G-F and WT primary hippocampal cultures, grown on MEAs, was regularly recorded over a 56 days-in-vitro culture maturation period. Early AppNL-G-F hippocampal hyperexcitability was recapitulated in this isolated culture system as evidenced by several indicative metrics, pertinently, through altered electrode- and network-level bursting dynamics. This translated to AppNL-G-F in vitro networks having increased functional connectivity but disrupted network topology and decreased efficiency. Moreover, conditioned AppNL-G-F media exchanged to WT cultures was sufficient to induce hyperexcitability, potentially implicating soluble Aβ as a mechanistic driver. 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