Changes In Other Molecular Markers In Schizophrenia

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While the focus of the present review is on the relationship between presynaptic proteins and neuropsychiatric disorders, this represents an analysis at just one level of these complex diseases. In the case of schizophrenia, there is also substantial interest at the neural "circuit" level. In particular, there has been recent interest in the nature of inhibitory circuits within the dorsolateral prefrontal cortex (DLPFC), and how alterations in these circuits may lead to cognitive deficits (reviewed in detail by Lewis and colleagues in ref. 79). Primate studies demonstrate that GABAergic interneurons in the DLPFC appear to play an essential role in working memory processes, by regulating both the spatial and temporal electrophysiological activity of surrounding pyramidal neurons. Multiple postmortem human studies have revealed that levels of glutamic acid decarboxylase (GAD67), an enzyme that synthesizes GABA and is specific to interneurons in the frontal cortex, is significantly decreased in the DLPFC in schizophrenia. This phenomenon is observed predominantly in DLPFC layers 3-5, wherein the number of GABAergic interneurons that express detectable levels of GAD67 is significantly reduced in schizophrenia, although absolute levels of GAD67 mRNA are similar to controls in those remaining neurons that do express detectable levels.

Synaptic Plasticity

Figure 26.2. Maps of the Distribution of Hippocampal Subfields with Statistically Significant (P < 0.05) Correlations Between Presynaptic Protein Levels and Specific Domains of Cognitive Dysfunction in Schizophrenia. Abbreviations: S25, SNAP-25; Cx1, complexin I; Cx2, complexin II; r, Spearman correlation coefficient; R1, R2, and R3, clinical dementia ratings for memory, orientation, and judgment, respectively. See Colorplate 12.

Figure 26.2. Maps of the Distribution of Hippocampal Subfields with Statistically Significant (P < 0.05) Correlations Between Presynaptic Protein Levels and Specific Domains of Cognitive Dysfunction in Schizophrenia. Abbreviations: S25, SNAP-25; Cx1, complexin I; Cx2, complexin II; r, Spearman correlation coefficient; R1, R2, and R3, clinical dementia ratings for memory, orientation, and judgment, respectively. See Colorplate 12.

Studies of frontal GABAergic interneurons revealed that there are multiple subtypes, which can be classified based on both neuroanatomical and electrophysiological properties, as well as the presence of the three calcium-binding proteins parvalbumin, calbindin, and calretinin. An analysis of the different subtypes of GABA interneurons, on a layer-by-layer basis in the DLPFC, indicates that parvalbumin expression is significantly decreased in layers 3 and 4 in schizophrenia, although the density of neurons expressing the gene was unaltered. However, of interest, it was noted that GAD67 mRNA was mostly reduced in neurons with lower levels of parvalbumin mRNA, suggesting that this class of neurons may be impaired by dysregulation of a number of related genes important for functional activity. These findings remain to be evaluated in alternate brain regions, such as the hippocampus, where evidence for global decreases in GABA markers is mixed, perhaps in part because of the greater macroarchitectural complexity of the region80.

There is now converging evidence that functional alterations in GABAergic interneurons in schizophrenia may be related to additional molecular changes that have been reported post mortem in schizophrenia. For instance, one of the more consistent findings in schizophrenia has been decreased levels of the protein reelin in multiple brain regions, including frontal cortex, hippocampus, and cerebellum81. This protein plays an important role in the development of laminated brain structures, although its function in adulthood remains unknown. Loss of the protein, or its receptors, in rodent paradigms results in behavioral and anatomical deficits homologous to those of schizophrenia82,83. In the adult brain, reelin is expressed predominantly by GABAergic interneurons, and it was recently demonstrated that levels of reelin were decreased in GAD67-expressing interneurons in cortex. These interneurons also overexpress DNA-methyltransferase 1 (DNMT1), which contributes to promoter CpG island hypermethylation, causing a downregulation of promoter functions and possibly resulting in lower levels of GAD67 and reelin mRNA expression84.

Genetic studies have also implicated a number of genes in the etiology of schizophrenia. Amongst these, one that has received much attention is the neuregulin 1 (NRG1) gene, which was identified by positional cloning as a susceptibility gene - an effect replicated in different ethnic populations, although sometimes with different haplotypes. The gene encodes a set of at least 15 known proteins, which act through the erbB family of membrane bound tyrosine kinase receptors. This class of receptors includes four genes, erbB1-4, although NRG1 only binds effectively to erbB3 and erbB4. Altered expression of erbB3 has been noted in the prefrontal cortex in schizophrenia. While the functional role of the NRG1/erbB complex remains under investigation, it is presently known to have diverse functions, including neural development and synaptic plasticity85.

There is clearly opportunity to integrate the above observations in schizophrenia with our findings of regional alterations in presynaptic proteins. The reduced expression of GABAergic interneuron markers in the DLPFC in schizophrenia is consistent with our report of decreased levels of Cx I in the frontal cortex in schizophrenia. As Cx I is found mainly in inhibitory terminals, and is expressed in the same layers as parvalbumin, a possible connection between reduced levels of Cx I in parvalbumin/GAD67 expressing interneurons is worthy of further study. Similarly, reduced levels of Cx I in both the frontal cortex and hippocampus may be associated with a loss of reelin in GABAergic interneurons. While the physiological role of NRG1/erbB in synaptic plasticity continues to be determined, the presynaptic proteins SNAP-25 and Cx I/II represent promising candidates for co-investigation.

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