Taylor, Charlotte
(2024)
A link between NMDA receptor hypofunction and GABAergic inhibition in the modulation of cognition: a comparison of neural and cognitive changes in rat models of NMDA receptor hypofunction and of prefrontal and hippocampal neural disinhibition.
PhD thesis, University of Nottingham.
Abstract
NMDA receptor (NMDAR) hypofunction and impaired GABAergic inhibition, so-called neural disinhibition, in the hippocampus and prefrontal cortex, have both been implicated in the pathophysiology of schizophrenia. Moreover, it has been suggested that NMDAR hypofunction and neural disinhibition are mechanistically linked and may converge on a common pathological hub. NMDAR hypofunction in rodents has been reported to mimic certain aspects of cognitive deficits associated with schizophrenia, alongside pathological reductions in hippocampal and prefrontal GABAergic markers. Given the importance of GABAergic inhibition in the hippocampus and prefrontal cortex for a range of cognitive functions, hippocampal and prefrontal neural disinhibition may underlie some of the cognitive deficits found in rodent models of NMDAR hypofunction. Here, we examined the overarching hypothesis that NMDAR hypofunction impairs cognition by causing neural disinhibition in the hippocampus and prefrontal cortex. In chapter 1, we reviewed the current evidence for this hypothesis, which demonstrated a compelling case for neural disinhibition in acute and neurodevelopmental models of NMDAR hypofunction. However, importantly, studies investigating the impact of sub-chronic NMDAR hypofunction on GABAergic function were equivocal in support of the hypothesis, and the role of these processes in mediating cognition on the watermaze delayed-matching-to-place (DMP) and novel object recognition (NOR) task, respectively, had not been investigated. In subsequent chapters, we aimed to address the hypothesis experimentally, by comparing and examining the cognitive and neural changes in rat models of sub-chronic NMDAR hypofunction and regional neural disinhibition.
In chapter 2, we examined the impact of NMDAR hypofunction, caused by sub-chronic treatment with phencyclidine (scPCP), in rats on the watermaze DMP task. Sub-chronic PCP treatment did not disrupt hippocampal rapid place learning performance. This contrasts with the marked impairments observed following acute pharmacological hippocampal disinhibition and suggests that hippocampal disinhibition is not a pronounced feature of the scPCP model. In chapter 3, we used high throughput simple western analysis to determine the protein levels of key GABAergic biomarkers, GAD67 and parvalbumin, in the brains of the scPCP treated rats used for behavioural studies in chapter 2. No changes in GAD67 or parvalbumin protein expression were found in the prefrontal cortex or dorsal region of the hippocampus. In the intermediate to ventral hippocampus, GAD67 was found to be reduced in female, but not male, rats, suggesting that scPCP treatment may have sex-specific neuropathological effects. Importantly, however, in the scPCP treated rats which underwent watermaze DMP testing, parvalbumin was found to be increased in the intermediate to ventral hippocampus. Overall, our investigations into GABAergic protein expression changes following NMDAR hypofunction revealed limited evidence for neural disinhibition in the prefrontal cortex and hippocampus. In chapter 4, we investigated whether scPCP treatment results in functional alterations to hippocampal neural activity. Using evoked in vivo recordings under urethane anaesthesia, we applied low frequency train stimulation to the subiculum or CA3 region, with the aim of examining instances of reverberatory responses as a measure of the overall excitability of hippocampal circuits. This study revealed evidence of reverberation in both treatment groups, indicating intact fibre pathways in scPCP treated rats. However, a preliminary analysis did not indicate clear-cut changes in hippocampal excitability following scPCP treatment. Finally, in chapter 5, we investigated whether neural disinhibition in the medial prefrontal cortex, dorsal or ventral hippocampus may account for the NOR deficits reported widely in the scPCP model. Neural disinhibition or functional inhibition was induced in rats via local infusion of picrotoxin or muscimol, respectively, and NOR performance compared using a within-subjects design. We found that hippocampal, but not prefrontal, GABAergic inhibition was required for intact NOR. This finding suggests that hippocampal GABAergic deficits may contribute, in part, to NOR deficits found in NMDAR hypofunction models.
Thus, the experiments reported in chapters 2-5 provide limited evidence for a link between NMDAR hypofunction and neural disinhibition in the hippocampus and prefrontal cortex in the modulation of cognition. The finding that hippocampal, but not prefrontal, GABAergic inhibition is required for intact NOR performance suggests that hippocampal GABAergic impairments could contribute to scPCP-induced NOR deficits. However, the lack of a watermaze DMP impairment in scPCP treated rats, combined with weak post-mortem evidence for reduced GABAergic markers, does not support a marked impairment of hippocampal GABA function in scPCP treated rats. Overall, our findings do not support that scPCP treatment leads to pronounced hippocampal disinhibition or that neural disinhibition in the prefrontal cortex or hippocampus plays a major role in cognitive deficits caused by sub-chronic NMDAR hypofunction.
| Item Type: |
Thesis (University of Nottingham only)
(PhD)
|
| Supervisors: |
Bast, Tobias
Moran, Paula
Harte, Michael
Gigg, John |
| Keywords: |
Neural disinhibition, GABA, NMDA receptor hypofunction, Hippocampus, Prefrontal cortex, Cognition, Schizophrenia |
| Subjects: |
B Philosophy. Psychology. Religion > BF Psychology
Q Science > QP Physiology > QP351 Neurophysiology and neuropsychology |
| Faculties/Schools: |
UK Campuses > Faculty of Science > School of Psychology |
| Item ID: |
77029 |
| Depositing User: |
Taylor, Charlotte
|
| Date Deposited: |
23 Jul 2024 04:40 |
| Last Modified: |
23 Jul 2024 04:40 |
| URI: |
https://eprints.nottingham.ac.uk/id/eprint/77029 |
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