Disrupted hippocampal-prefrontal synchrony in a neurodevelopmental animal model of schizophrenia
Temporal synchronisation of neural activity is proposed to provide an integrative mechanism for spatially separated neural processing in the brain. In individuals with schizophrenia, a breakdown in the integration of information processes due to aberrant synchronous activity has been proposed to underlie a range of deficits in the disorder. Through the application of in vivo electrophysiological techniques, this research examined putative biological mechanisms underlying this disrupted synchrony in a neurodevelopmental animal model. The Maternal Immune Activation (MIA) model of schizophrenia is derived from epidemiological evidence of increased risk of schizophrenia in adulthood following prenatal exposure to infection and is induced through a single injection of the synthetic immune system activator polyriboinosinic-polyribocytidylic acid in pregnant rat dams.Experiment One investigated long-range neural synchrony between brain regions with known pathology in schizophrenia - the hippocampus (HPC) and prefrontal cortex (mPFC) – in adult MIA offspring. Using in vivo single-unit and local field potential (LFP) recordings, we demonstrated that in utero exposure to MIA resulted in a reduction of long-range coherence between the mPFC and dorsal HPC in adult offspring during a basic foraging task. Further, we showed a deficit in the timing and phase of firing of single-unit activity in the mPFC to both local and long-range theta and gamma oscillations. A novel correlation between pre-pulse inhibition (PPI) of the startle response and low-gamma coherence between the mPFC and dorsal HPC was also found. Experiment Two revealed that the reduction in mPFC-dorsal HPC coherence in MIA animals did not appear to represent a global breakdown in coupling between regions, as coherence between the monosynaptically connected ventral HPC and mPFC remained intact. Western blot and dual-label immunofluorescence analysis further revealed that this pattern of aberrant synchronous activity was mirrored by a reduction in the expression of the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD)67, and the calcium-binding protein parvalbumin (PV), within PV-positive interneurons in the dorsal HPC that was not present in the ventral HPC. Building on the novel association identified in Experiment One between aberrant gamma coherence and disrupted PPI, Experiment Three investigated mPFC-dorsal HPC synchrony recorded during the PPI paradigm and critically during the processing of the pre-pulse and the startle stimuli. Greater theta coherence occurring during the processing of the pre-pulse, and greater gamma coherence during the startle stimulus presentation, were associated with a greater degree of inhibition of the behavioural startle response. Experiment Four demonstrated that the deficits in long-range synchrony identified in adult MIA offspring were ameliorated by the atypical antipsychotic, clozapine, in a dose-dependent fashion. This effect appeared to depend on the mPFC, suggesting a possible mechanism through which this drug may exert its therapeutic effects. Collectively, this research highlights a potentially critical disruption in communication between the mPFC and HPC, two regions functionally involved in higher-order cognitive processes, as a factor in schizophrenia. Further, it demonstrates that the MIA model can mirror relevant pathological symptoms of the human schizophrenia condition, thereby providing a platform from which to explore cellular level deficits in the disorder.
Advisor: Bilkey, David
Degree Name: Doctor of Philosophy
Degree Discipline: Psychology
Publisher: University of Otago
Keywords: Schizophrenia; synchrony; maternal immune activation; hippocampus; prefrontal cortex; Poly I:C; animal model; neurodevelopment
Research Type: Thesis