Evidence for a deficit in cholinergic interneurons in the striatum in schizophrenia

Neurochemical and functional abnormalities of the striatum have been report ed in schizophrenic brains, but the cellular substrates of these changes ar e not known. We hypothesized that schizophrenia may involve an abnormality in one of the key modulators of striatal output, the cholinergic interneuro n. We measured the densities of cholinergic neurons in the striatum in schi zophrenic and control brains in a blind analysis, using as a marker of this cell population immunoreactivity for choline acetyltransferase, the synthe tic enzyme of acetylcholine. As an independent marker, we used immunoreacti vity for calretinin, a protein which is co-localized with choline acetyltra nsferase in virtually all of the cholinergic interneurons of the striatum. A significant decrease in choline acetyltransferase-positive and calretinin -positive cell densities was found in the schizophrenic cases compared with controls in the striatum as a whole [for the choline acetyltransferase-pos itive cells: controls: 3.21 +/- 0.48 cells/mm(2) (mean +/- S.D.), schizophr enics: 2.43 +/- 0.68 cells/mm(2):, P < 0.02]. The decrease was patchy in na ture and most prominent in the ventral striatum (for the choline acetyltran sferase-positive cells: controls: 3.47 +/- 0.59 cells/mm2, schizophrenics: 2.52 +/- 0.64 cells/mm(2); P < 0.005) which included the ventral caudate nu cleus and nucleus accumbens region. Three of the schizophrenic cases with t he lowest densities of cholinergic neurons had not been treated with neurol eptics for periods from more than a month to more than 20 years. A decrease in the number or function of the cholinergic interneurons of the striatum may disrupt activity in the ventral striatal-pallidal-thalamic-pr efrontal cortex pathway and thereby contribute to abnormalities in function of the prefrontal cortex in schizophrenia. (C) 1999 IBRO. Published by Els evier Science Ltd.