Increased expression of Kalirin-9 in the auditory cortex of schizophrenia subjects: Its role in dendritic pathology

Abstract

Reductions in dendritic arbor length and complexity are among the most consistently replicated changes in neuronal structure in post mortem studies of cerebral cortical samples from subjects with schizophrenia, however, the underlying molecular mechanisms have not been identified. This study is the first to identify an alteration in a regulatory protein which is known to promote both dendritic length and arborization in developing neurons, Kalirin-9. We found Kalirin-9 expression to be paradoxically increased in schizophrenia. We followed up this observation by overexpressing Kalirin-9 in mature primary neuronal cultures, causing reduced dendritic length and complexity. Kalirin-9 overexpression represents a potential mechanism for dendritic changes seen in schizophrenia.

A Role for Kalirin in the Response of Rat Medium Spiny Neurons to Cocaine

“…This would be expected from previous work on sympathetic neurons, because Kal7, Kal9, and Kal12 all increase both fiber numbers and branching complexity (May et al, 2002). However, overexpression of Kal9 in cortical neurons is reported to increase dendritic spine numbers, coupled with a small decrease in total dendrite length (Deo et al, 2012). A decrease in NR2B levels is observed in the hippocampus of Kal7 KO mice.…”

Dendritic spine alterations in schizophrenia

“…Although the magnitude of the increase was modest, it was present in 20/26 (77%) subject pairs evaluated. In contrast, total levels of kalrin-5, kalirin-12, and PAK1 were not affected [78;79]. Finding altered kalirin-9 in schizophrenia is supported by prior reports that rare missense mutations located within the region of the KALRN gene shared only by kalirin-9 and -12 have been associated with risk for schizophrenia [80].…”

“…Deo et al further evaluated the effects of sustained (2 week) over-expression of kalirin-9 in mature primary neuronal cultures. These studies recapitulated the reduced total dendritic length and reduced dendritic complexity seen in studies of schizophrenia, but did not cause a change in dendritic spine number [78]. In contrast, when kalirin-9 was overexpressed in immature neuronal cultures, it was associated with neurite elongation [81].…”

“…This latter principal was further highlighted by the observation that the effect of global knockout of kalirin isoforms on dendritic spine loss varies by cortical region and developmental age, presumably reflecting age and regional variation in the background of molecules signaling to the actin cytoskeleton [76;77]. Perhaps not surprisingly, then, when Deo et al evaluated protein levels of 4 kalirin isoforms, kalirin-5, -7, -9, and -12 in primary auditory cortex, a region in which dendritic spine loss has also been found in schizophrenia [78;79], levels of kalirin-7 were not altered in the schizophrenia subjects. Whether the differences in findings for kalirin-7 protein between Deo et al [78] and Rubio et al [71] result from regional variations in disease-related effects must at present await further attempted replications, as differences in the cohorts studied is also a plausible source of the discrepancy.…”

“…Perhaps not surprisingly, then, when Deo et al evaluated protein levels of 4 kalirin isoforms, kalirin-5, -7, -9, and -12 in primary auditory cortex, a region in which dendritic spine loss has also been found in schizophrenia [78;79], levels of kalirin-7 were not altered in the schizophrenia subjects. Whether the differences in findings for kalirin-7 protein between Deo et al [78] and Rubio et al [71] result from regional variations in disease-related effects must at present await further attempted replications, as differences in the cohorts studied is also a plausible source of the discrepancy.…”