Dr. Law and Colleagues Reply

To the Editor: Dr. Dwork and colleagues raise several interesting issues. We emphasized that our main conclusion was merely that the decrease in spinophilin mRNA provides a further indication that the site of molecular alterations in synapses in schizophrenia and mood disorders includes dendrites as well as presynaptic terminals. We also suggested, parsimoniously, that the reduction is probably related to the decreases in spine density, which the correspondents and others have clearly demonstrated. Given what is known of the functions of spinophilin, as outlined in their letter, we agree that the reduction in its mRNA is more likely to be a consequence than a cause of the lower spine density (i.e., fewer spines require synthesis of less spinophilin), as we pointed out in our article (p. 1862). The fact that the percentage decrement in spine density is much greater than the reduction of spinophilin mRNA can be explained, as Dr. Dwork and colleagues note, by the fact that changes in transcript abundance are often less than those of the encoded protein and that the subcellular difference in the targeting of proteins may exist. Along similar lines, the lack of change in microtubule-associated protein 2 mRNA that we find may signify that any putative changes in microtubule-associated protein 2 are translational or posttranslational in origin.

Dr. Dwork and colleagues proposed one cascade in which spinophilin is involved and regulated. However, this important basic work was largely derived from model systems, and the extent to which these molecular cascades are operating in the predicted manner in human hippocampal neurons is not known.

In summary, we did not advocate that spinophilin is a molecule with a specific or central etiological role in schizophrenia or mood disorder, and we were unaware of the complexity of spinophilin’s roles in dendritic function. Rather, as the title of the article stated, the aim was to complement and draw attention to the evidence that dendritic spines are part of the molecular and cellular neuropathology of schizophrenia and mood disorder—work at which Dr. Dwork and colleagues have been at the forefront. We are sure that they would agree that more studies are necessary to refine the evidence for dendritic (spine) pathology and to begin to reveal the biochemical pathways that underlie it.