TY - THES

T1 - Elucidating the impact of recently identified schizophrenia-risk GRIN2A gene variants on brain and GABAergic neurotransmitter system function

AU - Cazacu, Raul

PY - 2025

Y1 - 2025

N2 - Background: N-methyl-D-aspartate (NMDA) receptors are crucial in regulating multiple neurotransmitter systems. Grin2a variants were shown to alter NMDA receptor function, inducing downstream impairments in neurotransmitter systems including glutamate, GABAergic and monoaminergic neurotransmitter systems and contributing to schizophrenia. Understanding the effects of these variants on the NMDA receptor can be crucial in enhancing therapeutic strategies for schizophrenia. In this study, we investigated Grin2a variants, a missense mutation (Grin2a.RQ) and a nonsense mutation (Grin2a.QX) which have been linked to schizophrenia by an exome sequencing study.Materials and Methods: We assessed their impact on working-memory (WM), anxiety-like behaviour and locomotory movement using the Y-maze spontaneous alternation test (YMSAT) and the open field maze test (OFT), gene expression of markers involved in glutamatergic and GABAergic neurotransmitter systems and cerebral metabolism in key regions associated with schizophrenia using the 2-deoxyglucose (2-DG) before and after dextroamphetamine exposure. Results: Results revealed no impairments in WM and locomotor movement in the behavioural tests for either mouse model, findings consistent with the absence of significant findings between groups in gene expression. However, in Grin2a.RQ mice an anxiety-like behaviour across time was revealed, with mutant mice being more anxious than controls in the first 5 minutes of the test, findings not reproduced by the Grin2a.QX model. Moreover, Grin2a.RQ mice presented multiple significant alterations in cerebral metabolism, including reduced metabolism in in the anterior prelimbic cortex (aPrL) following exposure to dextroamphetamine and increased metabolism in the cingulate cortex (Cg1) under baseline conditions.Conclusion: Grin2a.RQ mice exhibited heightened anxiety in a novel environment that was habituated similar to controls, alongside reduced responsiveness to dextroamphetamine in the aPrL, which may indicate that dysfunction in the monoaminergic system in this region may impair emotional regulation, with compensatory activity from the Cg1 in order to maintain emotional responses and manage anxiety.

AB - Background: N-methyl-D-aspartate (NMDA) receptors are crucial in regulating multiple neurotransmitter systems. Grin2a variants were shown to alter NMDA receptor function, inducing downstream impairments in neurotransmitter systems including glutamate, GABAergic and monoaminergic neurotransmitter systems and contributing to schizophrenia. Understanding the effects of these variants on the NMDA receptor can be crucial in enhancing therapeutic strategies for schizophrenia. In this study, we investigated Grin2a variants, a missense mutation (Grin2a.RQ) and a nonsense mutation (Grin2a.QX) which have been linked to schizophrenia by an exome sequencing study.Materials and Methods: We assessed their impact on working-memory (WM), anxiety-like behaviour and locomotory movement using the Y-maze spontaneous alternation test (YMSAT) and the open field maze test (OFT), gene expression of markers involved in glutamatergic and GABAergic neurotransmitter systems and cerebral metabolism in key regions associated with schizophrenia using the 2-deoxyglucose (2-DG) before and after dextroamphetamine exposure. Results: Results revealed no impairments in WM and locomotor movement in the behavioural tests for either mouse model, findings consistent with the absence of significant findings between groups in gene expression. However, in Grin2a.RQ mice an anxiety-like behaviour across time was revealed, with mutant mice being more anxious than controls in the first 5 minutes of the test, findings not reproduced by the Grin2a.QX model. Moreover, Grin2a.RQ mice presented multiple significant alterations in cerebral metabolism, including reduced metabolism in in the anterior prelimbic cortex (aPrL) following exposure to dextroamphetamine and increased metabolism in the cingulate cortex (Cg1) under baseline conditions.Conclusion: Grin2a.RQ mice exhibited heightened anxiety in a novel environment that was habituated similar to controls, alongside reduced responsiveness to dextroamphetamine in the aPrL, which may indicate that dysfunction in the monoaminergic system in this region may impair emotional regulation, with compensatory activity from the Cg1 in order to maintain emotional responses and manage anxiety.

U2 - 10.17635/lancaster/thesis/2754

DO - 10.17635/lancaster/thesis/2754

M3 - Master's Thesis

PB - Lancaster University

ER -