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).