Dissanayake, Watuthanthrige Dilshani Nadira
(2008)
Sensory gating in the hippocampus and the medial prefrontal cortex.
PhD thesis, University of Nottingham.
Abstract
Sensory gating is a mechanism by which irrelevant sensory information is filtered in the brain, enabling efficient information processing. The auditory conditioning-test paradigm, an index of sensory gating, measures the reduction in the auditory-evoked response (AER) produced by a test stimulus following an initial conditioning stimulus. Schizophrenic patients demonstrate a lack of attenuation of the test response measured in the P50 component of the cortical auditory-evoked potential. The N2/N40 auditory-evoked potential recorded from rat hippocampus is considered homologous to the human P50 wave. Altered glutamatergic neurotransmission and the endocannabinoid system have been implicated in the pathogenesis of schizophrenia with structural and functional abnormalities in the hippocampus and the medial prefrontal cortex (mPFC).
The current study examined sensory gating using auditory conditioning-test paradigm in the dentate gyrus (DG) and the CA3 region of the hippocampus and in the medial prefrontal cortex (mPFC) before and after administration of N-Methyl- D-Aspartate (NMDA) receptor antagonist phencyclidine (PCP; 1 mg/kg, i.p) or the cannabinoid agonist WIN55,212-2 (1.2mg/kg, i.p).
Electrophysiological recordings were conducted in Lister hooded rats, under isoflurane anaesthesia, during the presentation of paired auditory stimuli. Extracellular action potential spikes and local field potentials (LFPs) were recorded simultaneously using multi-electrode arrays and the effects of acute administration of PCP (1 mg/kg, i.p) or WIN55,212-2 (1.2mg/kg, i.p) was determined. Gating of the N2 wave was assessed by measuring the ratio of the Test to Conditioning response amplitude (T/C ratio); T/C ratio ≤ 50% was indicative of gating.
Robust auditory-evoked potentials were recorded from the hippocampal CA3 and DG regions and the mPFC; some rats demonstrated auditory gating while others failed to. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3.
PCP disrupted auditory gating in all three areas with a significant increase in test response amplitudes in the gating rats. PCP had no effect on T/C ratios in the non-gating rats. The atypical antipsychotic clozapine (5mg/kg, i.p) prevented PCP induced disruption of gating in the CA3, DG and mPFC. WIN55,212-2 disrupted auditory gating with a significant increase in test response amplitudes in the gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A (1mg/kg, i.p) prevented WIN55,212-2 induced disruption of gating. Neither clozapine nor SR141716A had any effects on the non-gating rats. Both PCP and WIN55,212- 2 disrupted gating of the single-unit responses in the CA3, DG and mPFC, effects which were prevented by the pre- administration of clozapine or SR141716A.
The non-gating rats may model some inhibitory deficits observed in schizophrenic patients. Administration of PCP disrupted auditory gating which was prevented by clozapine; similar deficits are observed in schizophrenic patients. Furthermore, cannabinoid receptor activation disrupted auditory gating which was prevented by CB1 receptor antagonism, suggesting the endocannabinoid system as a potential target for future clinical research in the treatment in schizophrenia.
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