Schizophrenia frontal cortex

Johnston-Wilson NLet al. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry 2000 5 142-149. 

Miller, C. L., Llenos, I. C., Dulay, J. R. et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis. 15 618-629, 2004. 

There are some indications that GABAergic axonal innervation is diminished in the cortex in schizophrenia. A deficit of GAD-immunoreactive puncta was reported in frontal cortex (Woo et al., 1998) and hippocampus (Todtenkopf Benes, 1998), while the cortical plexus of (GABAergic) parvalbumin-immunoreactive fibres is also diminished (Reynolds et al., 2001). The latter two studies reported a positive correlation of these measures of innervation with total antipsychotic drug exposure, indicative of protective or stimulatory effects of chronic drug treatment. 

Peter Liddle and his colleagues (2000) used positron emission tomography (PET) to study the effects of risperidone on the rate of metabolism on the ventral striatum, thalamus, and frontal cortex. Their subjects were eight neuroleptic-naive patients diagnosed with their first episodes of schizophrenia. 

Results Compared with placebo, risperidone produced reductions in metabolism in the left lateral frontal cortex and right medial frontal cortex in healthy subjects. Conjunction analysis reveals that these changes occurred at locations similar to the loci of change produced risperidone with schizophrenia. 

Because the reduction in metabolism in the medial frontal cortex produced by risperidone is associated with alleviation of positive symptoms in patients with schizophrenia, the observation of a reduction in metabolism at a similar site in healthy subjects supports the hypothesis that the antipsychotic effect of risperidone arises, at least in part, from a physiologic effect that occurs in both patients with schizophrenia and healthy subjects. 

From the earliest studies, there has been a somewhat consistent finding of hypoactivity in the frontal lobes and frontal cortex of neuroleptic-treated people with schizophrenia (Buchsbaum et al., 1982 Farkas et al., 1984 Wolkin et al., 1988, as reviewed in Andreasen, 1988 Wolkin et al., 1985). In most studies, the patients had long histories of neuroleptic treatment prior to the PET scans, and the drugs were temporarily stopped at the time. However, temporarily stopping neuroleptic treatment would not have reversed its long-standing and persistent suppressive effects on the frontal lobes. 

Using 3H-QNB as a marker for all five subtypes of the mAChRs, an early study reported a significant reduction in the level of mAChR-binding in the frontal cortex of subjects with schizophrenia compared with healthy controls (Bennett et al., 1979). This result was not replicated in two later studies, which reported an increased number of mAChRs in frontal cortex in medicated subjects with schizophrenia (Watanabe et al, 1983 Toru et al., 1988). 

Several studies have consistently implicated SNAP-25 in schizophrenia. Postmortem SNAP-25 protein was found to be decreased in the hippocampus (Young et al., 1998 Fatemi et al., 2001 Thompson et al., 2003a), prefrontal cortex (Thompson et al., 1998 Karson et al., 1999), temporal cortex (Thompson et al., 1998), anterior frontal cortex (Honer et al., 2002), and cerebellum (Mukaetova-Ladinska et al., 2002) of individuals with schizophrenia. Conversely, elevated SNAP-25 in cerebrospinal fluid of patients with schizophrenia was observed (Thompson et al., 1999 Thompson et al., 2003b). One study failed to find a change in SNAP-25 in the prefrontal cortex (Brodman s area 9) of individuals with schizophrenia, but did find an increase in individuals with bipolar disorder (Scarr et al., 2006). 

Postmortem studies of molecules involved in glutamate transmission have found abnormal expression at the transcript and protein levels in schizophrenia. However, these changes appear to be regional in nature with most changes localized to areas of the frontal cortex, the thalamus, and the limbic structures, with few findings of altered expression in the basal ganglia. 

The histamine system has been implicated in the pathophysiology of schizophrenia by several observations, including evidence for increased CNS metabolism of histamine (Prell et al., 1995), lower levels of H1 receptor expression in the frontal cortex, the striatum, and the thalamus as evaluated by positron emission tomography (Iwabuchi et al., 2005 Yanai and Tashiro, 2007), and the therapeutic efficacy of H3 antagonists on cognitive symptoms in patients with schizophrenia (Vohora, 2004 Esbenshade et al., 2006). Functionally, this... 

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