The microscopic studies described in this proposal are seeking to replicate and extend the investigator's previous investigations suggesting that schizophrenia may be a neurodevelopmental disorder involving a reduction of GABAergic interneurons and/or activity in the ACCx and other corticolimbic regions of schizophrenic brain. Because the dopamine (DA) and serotonin (5-HT) systems are also believed to play a role in the pathophysiology of schizophrenia and both transmitters may act directly on GABA neurons, the proposed studies will test the hypothesis that a reduction of GABAergic interneurons during development may be associated with a """"""""mis-wiring"""""""" of DA and 5-HT inputs to these interneurons, particularly in layer II of schizophrenia ACCx.
In Specific Aim I, the investigator will use a combination of cell counting and receptor binding autoradiography (GABA-A) to replicate, and in situ hybridization (glutamate decarboxylase (GAD)67 messenger ribonucleic acid) to extend her previous findings suggesting a loss of GABAergic interneurons.
In Specific Aims II and III, the studies described will evaluate whether there are additional changes in the interaction of DA and 5-HT inputs to intrinsic cortical neurons in schizophrenia. The numbers of tyrosine hydroxylase- (TH) and tryptophan hydroxylase-immunoreactive varicosities (TrypH)-IRv in apposition with pyramidal (PNs) and nonpyramidal (NPs) neuron cell bodies will be used as presynaptic markers, while the activity of D1, D2, 5-HT1A and 5-HT2A receptors on these respective cell types will be used as postsynaptic markers for these two monoaminergic inputs. The potential confounding effects of age and postmortem interval will be controlled for using a standard battery of statistical evaluations, while the contribution of neuroleptic exposure will be assessed by comparing data from drug-treated versus drug-free schizophrenics. To compensate for the small number of drug-free schizophrenics available at any given time, a central database will be used to accumulate data from such cases, so that meta-analytic approaches can be used to combine datasets acquired over the period of this grant and beyond.
Specific Aim I V will provide a second strategy to control for neuroleptic effects by comparing findings for the GABA, DA and 5-HT systems from the postmortem studies described above with similar data obtained from Area 24 of rats treated both acutely and chronically with typical (haloperidol) and atypical (clozapine) neuroleptic drugs. Overall, these studies will contribute to our understanding of how the intrinsic circuitry of ACCx and other corticolimbic regions may be altered in schizophrenia and will hopefully provide new insights into the nature and treatment of this unique and perplexing disorder.
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