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Molecular Mechanisms of Cognitive Impairment in a Maternal Immune Activation Model for Schizophrenia in the Rat.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	Molecular Mechanisms of Cognitive Impairment in a Maternal Immune Activation Model for Schizophrenia in the Rat./
作者:	Woods, Rebecca M.
面頁冊數:	1 online resource (501 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-09, Section: A.
Contained By:	Dissertations Abstracts International85-09A.
標題:	Child development. -
電子資源:	click for full text (PQDT)
ISBN:	9798381853285

Molecular Mechanisms of Cognitive Impairment in a Maternal Immune Activation Model for Schizophrenia in the Rat.
Woods, Rebecca M.

Molecular Mechanisms of Cognitive Impairment in a Maternal Immune Activation Model for Schizophrenia in the Rat. - 1 online resource (501 pages)

Source: Dissertations Abstracts International, Volume: 85-09, Section: A.

Thesis (Ph.D.)--The University of Manchester (United Kingdom), 2023.

Includes bibliographical references

Schizophrenia is a debilitating neuropsychiatric disorder with heterogenous symptoms across three key domains: positive, negative and cognitive symptoms. Current therapeutic interventions rely primarily on psychopharmaceuticals (e.g., antipsychotics) in combination with psychotherapy. While these approaches have been successful at managing positive and more recently negative, symptom domains, they provide limited benefit for cognitive symptoms. Lack of efficacious therapeutic approaches owes particularly to the complex aetiology of schizophrenia, comprising both genetic and environmental risk factors. Critically, schizophrenia is hypothesised to arise from perturbed neurodevelopment, with maternal infection, resulting in maternal immune activation (MIA), recognised as a crucial risk factor for schizophrenia in MIA-exposed foetuses. Preclinical models of this paradigm are essential for identification of causal mechanisms underscoring this risk and therefore identification of novel therapeutic targets. This thesis aimed to explore the developmental molecular mechanisms which mediate the relationship between MIA in uteroand later-life cognitive deficits in a rat model for MIA.The model used here induced MIA on gestational day (GD) 15 via administration of the viral mimetic, poly(I:C), in pregnant Wistar rats, with acute MIA measured by changes in plasma cytokine concentrations and weight in the 24h period post-exposure. Adolescent and adult offspring cognitive performances were measured through various behavioural tasks to identify phenotypes of relevance for schizophrenia. Placental and foetal brain samples were collected at GD15, 16 and 21 and postnatal cortex samples collected across a longitudinal timeline: at postnatal day 1 (infancy), 21 (juvenile), 35 (adolescence), 100-175 (adulthood) to assess ongoing neurodevelopmental alterations in response to MIA. Accordingly, molecular measurements included: metabolite quantification, DNA methylation profiling, relative gene and protein expression, enzymatic activity assays and cell density/morphology changes.Poly(I:C) administration induced acute MIA, with elevations in plasma pro-inflammatory cytokines IL-6 and TNFI± 3h post-exposure and subsequent weight loss 6-24h post-exposure. MIA-exposure in uteroinduced a distinct prenatal phenotype consisting of foetal neuroinflammatory dysregulation coincident with disturbances in placental and foetal brain one carbon metabolism pathways. Prenatal perturbations to these processes appear to alter glial cell differentiation and development, seemingly driven by altered DNA methylation of glial-specific genes. Critically, altered epigenetic patterns at glial-specific genes persist throughout the postnatal period, resulting in altered transcriptomic and proteomic profiles of these cells across postnatal neurodevelopment, alongside altered cell densities and morphologies. Dysfunctional glia, in turn, associate with malformed myelin and extracellular matrices which precipitate loss of synaptic plasticity and early closure of the prefrontal cortex (PFC) critical period, an essential developmental period for correct development of higher cognitive functions. Reduced plasticity in this period precedes excitatory/inhibitory imbalance and inflammatory dysregulation in adulthood, manifesting alongside a robust PFC-mediated cognitive deficit in the attentional set-shifting task, indicative of executive function deficits, of relevance to schizophrenia. Notably, the characterised PFC molecular phenotype in MIA-exposed adults demonstrates key similarities to findings from schizophrenia patients, including: parvalbumin interneuron dysfunction, glutamatergic receptor imbalance, inflammatory dysregulation and demyelination. Likewise, differentially methylated genes in the adult PFC were significantly enriched for schizophrenia-risk genes; together supporting the relevance of the model for schizophrenia. Critically, the results postulate a window between adolescence and adulthood, where neuro-molecular abnormalities are present alongside preliminary evidence for elevated systemic IL-6 protein as a biomarker, prior to the development of cognitive deficits, which could be utilised to target interventions which prevent development of, or ameliorate, schizophrenialike behaviours in MIA-offspring. Overall, the findings demonstrate a robust MIA model, with molecular and behavioural phenotypes that offers promise as a preclinical schizophrenia model.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381853285Subjects--Topical Terms:

554713
Child development.
Index Terms--Genre/Form:

554714
Electronic books.

Molecular Mechanisms of Cognitive Impairment in a Maternal Immune Activation Model for Schizophrenia in the Rat.
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