Novel insights into the role of the gut microbiome on hippocampal synaptic plasticity

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dc.check.date2026-05-31
dc.contributor.advisorCryan, John
dc.contributor.advisorO'Riordan, Ken
dc.contributor.authorCollins, Michael K.en
dc.contributor.funderScience Foundation Ireland
dc.contributor.funderIrish Research Council
dc.date.accessioned2025-02-14T12:07:22Z
dc.date.available2025-02-14T12:07:22Z
dc.date.issued2024en
dc.date.submitted2024
dc.description.abstractSynaptic plasticity especially within the hippocampus is a central process of the learning machinery of the brain. The microbiota gut-brain axis has emerged as an important regulator of hippocampal function yet there exists a paucity of information on how and when this axis can affect hippocampal synaptic plasticity. New strides need to be taken to develop successful interventions for human diseases which feature dysregulation of synaptic plasticity and to understand when normal synaptic plasticity may be susceptible to altered regulation from the microbiota-gut brain axis. In this thesis we focused primarily on how adult synaptic plasticity in the hippocampus may be affected by microbiome interventions. We also assessed the microbiome’s role in altering the developmental trajectory of the hippocampal transcriptome with a special focus on plasticity-related pathways. Firstly, we used germ free mice to examine how growing up without a gut microbiome has altered synaptic plasticity with hippocampal slice electrophysiology. While basal synaptic efficacy and pre-synaptic short-term plasticity appear normal, we found a deficit of hippocampal long-term potentiation in slices from male germ-free mice whereas slices from female animals produced this plasticity process relatively normally. However, the spike output of these neuronal populations remained normal, possibly indicating an altered excitation-inhibition balance or a homeostatic compensatory mechanism. Following this, we began to interrogate whether the microbiota’s ability to alter synaptic plasticity is developmentally wired or remains susceptible in adulthood. To this end we depleted the microbiome in adult life using either an antibiotic cocktail or a single antibiotic. This two-week microbiota intervention in adulthood produced only subtle effects on short-term plasticity and left LTP unchanged, demonstrating the robustness of hippocampal plasticity to the effects of microbiome depletion in adulthood. We then investigated how a local exposure to short-chain fatty acids (SCFAs), an abundantly produced class of microbial metabolite, may affect hippocampal synaptic plasticity in adulthood. Three SCFAs were tested, acetate, propionate, and butyrate at physiologically relevant concentrations. While no effect of acetate or propionate was found, butyrate-treated slices produced a greater degree of LTP in slices from both male and female mice. We hypothesized this effect was occurring through butyrate’s action at free fatty acid receptor 3 (FFAR3). However, when slices were pre-treated with an inhibitor of this receptor only slices from female mice reverted to producing normal levels of LTP, showing once again a sex-specific response to microbiome signals. Finally, we returned to the GF mouse model, examining four putative critical windows in early life, to establish how the microbiota changes the hippocampal transcriptome and metabolome. Metabolomic analysis revealed post-natal day (P) 21 to be the most differentially regulated in GF mice regardless of sex. GF status also significantly altered the hippocampal transcriptome with effects culminating at the oldest examined timepoint, P21. This effect was mirrored in a targeted enrichment analysis of pathways relating to synaptic plasticity. Unlike the metabolomic analysis however, transcriptomic analysis revealed a strong interaction of microbiome and sex with females showing the greatest differences despite a similarly altered metabolome. Overall, the results of this thesis provide novel insights into how the microbiome may alter hippocampal plasticity in adulthood and early life, with microbiome-induced effects often emerging in a sex-specific manner.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationCollins, M. K 2024. Novel insights into the role of the gut microbiome on hippocampal synaptic plasticity. PhD Thesis, University College Cork.
dc.identifier.endpage325
dc.identifier.urihttps://hdl.handle.net/10468/17040
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.project(SFI/12/RC/2273_P2)
dc.relation.projectIrish Research Council (Grant no. GOIPG/2021/942)
dc.relation.projectinfo:eu-repo/grantAgreement/SFI/SFI Research Centres/12/RC/2273/IE/Alimentary Pharmabiotic Centre (APC) - Interfacing Food & Medicine/
dc.rights© 2024, Michael Collins.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectSynaptic plasticity
dc.subjectGut microbiome
dc.subjectElectrophysiology
dc.subjectNeurodevelopment
dc.titleNovel insights into the role of the gut microbiome on hippocampal synaptic plasticity
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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