A link between NMDA receptor function and GABAergic inhibition in the modulation of cognition?
A link between NMDA receptor function and GABAergic inhibition in the modulation of cognition? A comparison of neural and cognitive changes in rat models of NMDA receptor hypofunction, neural disinhibition and maternal immune activation
This behavioural and integrative neuroscience project in rats will study the link between NMDA receptor function and hippocampal and prefrontal GABA inhibition in the modulation of cognition.
Both NMDA receptor hypofunction and reduced GABA inhibition, so-called neural disinhibition, have been implicated in cognitive disorders, including schizophrenia and age-related cognitive decline1,2. Furthermore, rodent models of NMDA receptor hypofunction are widely used in in pre-clinical research to discover new drug treatments for cognitive disorders, especially schizophrenia2.
Hippocampal and prefrontal GABA inhibition is required for cognitive functions, such as attention and memory1,3,5. NMDA receptors are required to maintain GABA inhibition, with NMDA receptor hypofunction in rodents reducing hippocampal and prefrontal GABA markers2,6. Based on these lines of evidence, the experiments in this project will examine the overarching hypothesis that NMDA receptor hypofunction impairs cognition by causing hippocampal and prefrontal neural disinhibition6.
The student will combine neurobiological (including electrophysiological and histological) and behavioural methods in rat models of NMDA receptor hypofunction (injection of NMDA receptor antagonist phencyclidine2) and of hippocampal and prefrontal neural disinhibition (intracerebral infusion of GABA antagonist picrotoxin3,5). S/he will also examine NMDA and GABA markers in the maternal immune activation model, which shows cognitive deficits that may be linked to GABA and glutamatergic changes4.
The project will be supervised by Tobias Bast and Paula Moran (Psychology, University of Nottingham) and Jo Neill and John Gigg (b-neuro at University of Manchester). The student will join the Behavioural Neuroscience Group in the School of Psychology at the University of Nottingham and will spend 3-6 months with b-neuro. The successful applicant will benefit from a stipend enhancement provided by b-neuro (£1,000 per year) in addition to the stipend at the RCUK rate (2019/20, £15,009 per year). Please email tobias.bast@nottingham.ac.uk for informal inquiries.
Selected reading
1. Bast T, Pezze M, & McGarrity S (2017) Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition. British journal of pharmacology, 174(19), 3211-3225.
2. Cadinu D, Grayson B, Podda G, Harte MK, Doostdar N, & Neill JC (2018) NMDA receptor antagonist rodent models for cognition in schizophrenia and identification of novel drug treatments, an update. Neuropharmacology 142, 41-62.
3. McGarrity S, Mason R, Fone KC, Pezze M & Bast T (2017) Hippocampal neural disinhibition causes attentional and memory deficits. Cerebral Cortex, 27(9), 4447-4462.
4. Murray KN, Edye ME, Manca M, Vernon AC, Oladipo JM, Fasolino V, Knuesel I,... & Neill JC (2019) Evolution of a maternal immune activation (mIA) model in rats: Early developmental effects. Brain, behavior, and immunity, 75, 48-59.
5. Pezze M, McGarrity S, Mason R, Fone KC & Bast T (2014) Too little and too much: hypoactivation and disinhibition of medial prefrontal cortex cause attentional deficits. Journal of Neuroscience, 34(23), 7931-7946.
6. Reynolds GP & Neill JC (2016) Modelling the cognitive and neuropathological features of schizophrenia with phencyclidine. Journal of Psychopharmacology, 30(11), 1141-1144
Please click here to apply for this project.