73,77 Putative mechanisms of glutamatergic involvement in the disorder center on interactions with dopamine78 and subtle forms of excitotoxicity.79 γselleck kinase inhibitor -Aminobutyric acid (GABA) In addition to the excitatory pathology implied by glutamatergic abnormalities, the major

inhibitory transmitter GABA has also been advocated, on the basis of alterations in receptor expression seen in the hippocampus and frontal cortex,80-82 as well as a possible loss81 or decreased activity83 of GABAergic neurons and the loss of GABAergic presynaptic terminals mentioned earlier.47 The latter studies illustrate the overlap between neurochemical and structural aspects Inhibitors,research,lifescience,medical of pathology, and emphasize that the one cannot be understood clearly without knowledge of the other. For example, consider Inhibitors,research,lifescience,medical a decrease in the

density of a receptor present on the dendritic spines of pyramidal neurons in schizophrenia: does this reflect a primary disturbance of the receptor, or is it secondary to a loss of dendritic spines, a generalized dysfunction of the spines, or even a pathology of the neuron itself? Postmortem studies Inhibitors,research,lifescience,medical have the unique potential to allow all these possibilities to be addressed, and therefore the nature of the abnormalities in schizophrenia to be understood; these advantages counterbalance, and must be offset against, the many difficulties of postmortem research. Methodological issues Postmortem studies of schizophrenia have an unenviable reputation of being

seriously flawed because of two main sorts of artifact: those due to perimortem changes, and those due to Inhibitors,research,lifescience,medical antipsychotic medication or other treatments. Perimortem confounders are a real but manageable problem.84 Depending on the parameter being measured, various individual factors are important. For example, for morphometric studies, Inhibitors,research,lifescience,medical the mode of tissue fixation and processing is important, whereas neurochemical and molecular targets are more affected by mode of death and hypoxia/ischemia. A range of experimental and statistical strategies are available to address these factors, and to allow the effects of schizophrenia to GSK-3 be distinguished from them.85 Confounding by antipsychotic drugs is unavoidable, in that, virtually all schizophrenics have (and should have) received treatment, during life, and the majority are on medication at the time of death. Such confounding is greatest in two areas: for dopamine and other neurochemical parameters, which are the target of the drugs; and for neuropathological studies in the striatum and substantia nigra, where there is clear postmortem and experimental evidence that antipsychotics induce neuronal and synaptic changes.86 However, for other studies and in other brain regions, antipsychotic effects are an overemphasized problem.