KCNQ/M channels in the midbrain dopaminergic system in the rat neonatal hippocampal lesion model of schizophrenia

Deemyad, Tara (2008) KCNQ/M channels in the midbrain dopaminergic system in the rat neonatal hippocampal lesion model of schizophrenia. Masters thesis, Memorial University of Newfoundland.

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Abstract

Increase in dopaminergic (DA) neurotransmission in the brain has been implicated in schizophrenia. One of the known mechanisms for promoting dopamine release is burst firing of DA cells. However, it is unclear whether alterations in firing patterns of DA cells are associated with the disease. In the present study at first I hypothesized that M current contributes to burst firing of DA cells in slices. I therefore studied the effect of M channel blockade on the firing behavior of DA cells in the ventral tegmental area. Then I hypothesized KCNQ channel expression in VTA DA cells in nVH lesion rats is reduced to promote the excitability of these cells. Therefore I examined the expression of KCNQ3, a subunit that forms heterodimeric channels with other subunits to carry M currents with much greater conductance, in rats that underwent ventral hippocampal lesion early in life which has been widely used as a rat model of schizophrenia. -- First, the effect of blocking M channels on the firing behavior was studies in horizontal brain slices that contained the ventral tegmental area using nystatin perforated patch clamp recording. Blocking the channel with linopirdine or XE-991 resulted in excitation of DA, but not GAB A cells in the ventral tegmental area. This increase firing was accompanied by a reduction of the medium hyperpolarizing afterpotential and a mild depolarization. In the majority of DA cells tested, blocking these channels also resulted in burst firing. -- Next, the expression of KCNQ3 channel in the ventral midbrain was studies in neonatal ventral hippocampal lesioned rats. Bilateral injection of ibotenic acid in the ventral hippocampus at postnatal 7 resulted in cell loss that was confirmed with Nissl staining at the end of the experiment. The lesioned group had a gradual increase in the deficit in prepulse inhibition tested at 35, 49 and 56 postnatal days, a hallmark of this model. The brains were processed immunohistochemically for the expression of KCNQ3 subunits in the midbrain. I found that the number of cells expressing KCNQ3 channels was decreased in the ventral tegmental area of the lesion group as compared with the sham group. Double immunofluorescence labeling with tyrosine hydroxylase and KCNQ3 showed a high percentage of colocalization in dorsal tier of ventral tegmental area, suggesting the reduction in KCNQ3 channel expression occurs in DA cells. In contrast, in the lesion group, the number of KCNQ3 positive cells was significantly increased in the red nucleus and the oculomotor nucleus. -- In conclusion, the results in this thesis suggest that neonatal hippocampal lesion leads to decreased expression of KCNQ3 channels in DA cells that may result in increased excitability and/or increased burst firing to enhance DA transmission. This maybe one of the mechanisms by which the DA system becomes overactive in schizophrenic brain.

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