Memory-Related Synaptic and Oscillatory Alterations in the Hippocampus of a Rat Model for Schizophrenia

Abstract

Schizophrenia is a severe psychiatric disorder characterised by cognitive deficits that are poorly managed by current treatments. A growing body of evidence suggests that these impairments may stem from NMDA receptor (NMDAR) hypofunction, particularly within the hippocampus, where synaptic plasticity and network coordination play key roles in memory. This thesis investigated how sub-chronic NMDAR hypofunction, modelled by sub-chronic phencyclidine (scPCP) treatment, affects hippocampal function at behaviral, synaptic and network levels, and whether voluntary aerobic exercise can improve these deficits. Using behavioural, in vivo electrophysiological and oscillatory analyses, three studies were conducted in adult female rats. In the first study, scPCP-treated rats displayed impaired novel object recognition (NOR), reduced CA3-CA1 long-term potentiation (LTP) and stronger depotentiation under urethane anaesthesia. Short-term plasticity assessed via paired-pulse facilitation was preserved, indicating a selective disruption of synaptic strengthening. The second study investigated whether six weeks of voluntary wheel running could restore hippocampal function in scPCP rats. Exercise led to partial improvements in NOR performance, LTP and depotentiation, suggesting enhanced postsynaptic stability, thoug not a full reversal of scPCP-induced impairments. The third study recorded hippocampal local field potentials during NOR performance in awake, behaving animals. In neurotypical rats, theta-gamma phase-amplitude coupling in the CA1 region differentiated between novel and familiar object exploration, consistent with flexible encoding and retrieval states. This dynamic modulation was blunted in scPCP rats, who failed to exhibit distinct oscillatory patterns between conditions. Moreover, synaptic plasticity remained impaired in awake recordings, reinforcing the persistence of LTP deficits in behaviourally relevant states. Together, these experiments demonstrate that sub-chronic NMDAR hypofunction leads to specific impairments in hippocampal synaptic strengthening and disrupts the flexible engagement of network rhythms during memory retrieval. While voluntary exercise shows potential to partially restore these functions, the overall findings point to enduring disruptions in hippocampal plasticity and coordination following NMDAR hypofunction.

Date of Award	23 Sept 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gigg (Main Supervisor) & Michael Harte (Co Supervisor)