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Reduced Spinophilin in Schizophrenia

To the Editor: Amanda J. Law, Ph.D., et al. (1) reported decreased mRNA for spinophilin in the hippocampal formation in patients with schizophrenia and mood disorders. The potential implications of this abnormality are curious since spinophilin is involved in limiting or decreasing the length of dendritic spines. Spinophilin immunoreactivity is predominantly (although not exclusively) localized to dendritic spines (2), for which it is a meaningful marker, with hippocampal spine density and spinophilin immunoreactivity both increasing in response to estrogen (3). However, spinophilin is not necessary for the formation of spines, which are increased in density in young spinophilin knockout mice or for their removal, since spine density returns to normal when such animals mature (4).

Spinophilin links protein phosphatase-1 to actin. Dephosphorylation of actin by protein phosphatase-1 leads to its disassembly (5), so the targeting of protein phosphatase-1 to actin is likely to result in fewer or shorter dendritic spines. Linking protein phosphatase-1 to actin also promotes dephosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (4). The subsequent decrease in the activity of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors should decrease calcium influx into the spine, reducing the phosphorylation of spinophilin by calcium-calmodulin kinase II and thereby enhancing its affinity for actin (6).

The reported subicular decrease in spinophilin mRNA in schizophrenia is approximately 30% (1). We observed a decrease of 75%–80% in the density of apical dendritic spines (plus a more modest decrease in apical dendritic arborization) (7), but the density of spines on basilar dendrites has not been measured. If the diminished pool of mRNA is supporting the synthesis of spinophilin for an even more diminished set of dendritic spines, increased synthesis of spinophilin, on a per-spine basis, might function to keep spine density reduced. Posttranscriptional mechanisms are also likely, as evidenced by estrogen-induced increases in spine density and spinophilin immunoreactivity, without altered levels of spinophilin mRNA (3).

References

1. Law AJ, Weickert CS, Hyde TM, Kleinman JE, Harrison PJ: Reduced spinophilin but not microtubule-associated protein 2 expression in the hippocampal formation in schizophrenia and mood disorders: molecular evidence for a pathology of dendritic spines. Am J Psychiatry 2004; 161:1848–1855[Abstract/Free Full Text]
2. Muly EC, Smith Y, Allen P, Greengard P: Subcellular distribution of spinophilin immunolabeling in primate prefrontal cortex: localization to and within dendritic spines. J Comp Neurol 2004; 469:185–197[CrossRef][Medline]
3. Lee SJ, Romeo RD, Svenningsson P, Campomanes CR, Allen PB, Greengard P, McEwen BS: Estradiol affects spinophilin protein differently in gonadectomized males and females. Neuroscience 2004; 127:983–988[CrossRef][Medline]
4. Feng J, Yan Z, Ferreira A, Tomizawa K, Liauw JA, Zhuo M, Allen PB, Ouimet CC, Greengard P: Spinophilin regulates the formation and function of dendritic spines. Proc Natl Acad Sci USA 2000; 97:9287–9292[Abstract/Free Full Text]
5. Fernandez A, Brautigan DL, Mumby M, Lamb NJ: Protein phosphatase type-1, not type-2A, modulates actin microfilament integrity and myosin light chain phosphorylation in living nonmuscle cells. J Cell Biol 1990; 111:103–112[Abstract/Free Full Text]
6. Grossman SD, Futter M, Snyder GL, Allen PB, Nairn AC, Greengard P, Hsieh-Wilson LC: Spinophilin is phosphorylated by Ca2+/calmodulin-dependent protein kinase II resulting in regulation of its binding to F-actin. J Neurochem 2004; 90:317–324[CrossRef][Medline]
7. Rosoklija G, Toomayan G, Ellis SP, Keilp J, Mann JJ, Latov N, Hays AP, Dwork AJ: Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry 2000; 57:349–356[Abstract/Free Full Text]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by DWORK, A. J. Articles by JONES, L. B. Search for Related Content PubMed Citation Articles by DWORK, A. J. Articles by JONES, L. B. Schizophrenia Spectrum Disorders Genetics Other Neuroanatomy

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