DIFFERENTIAL DISTRIBUTION OF TYROSINE-HYDROXYLASE FIBERS ON SMALL ANDLARGE NEURONS IN LAYER-II OF ANTERIOR CINGULATE CORTEX OF SCHIZOPHRENIC BRAIN

A series of recent postmortem investigations of the anterior cingulate cortex in schizophrenic brain have suggested that there may be a loss and/or impairment of inhibitory interneurons in layer II. It has been postulated that changes of this type could secondarily result in a re lative increase of dopaminergic inputs to GABAergic interneurons. To t est this hypothesis, an immunoperoxidase technique was developed to ex tensively and reliably visualize tyrosine hydroxylase-immunoreactive ( TH-IR) varicose fibers in human postmortem cortex. This method has bee n applied to the anterior cingulate (ACCx; Brodmann area 24) and prefr ontal (PFCx; Brodmann area 10) cortices from a cohort of 15 normal con trol and 10 schizophrenic cases. The number of TH-IR varicosities in c ontact with large neurons (LN), small neurons (SN), and neuropil (NPL) was blindly analyzed using a computer-assisted microscopic technique. There was no significant difference in density of TH-IR varicosities in apposition with either LN or SN cell bodies observed in either ACCx or PFCx of schizophrenics when compared to normal controls. The densi ty of varicosities was significantly reduced in NPL of layers V and VI in ACCx, but 2 neuroleptic-free cases did not show this change, sugge sting that these decreases of TH-IR varicosities may be related to ant ipsychotic effects on corticostriatal projection cells in this region. When the density of TH-IR varicosities on SNs was compared to that ob served on LNs, both groups showed a higher density on SNs. In ACCx, th is pattern was much more pronounced for the schizophrenic group, parti cularly in layer II where the density on SNs was three times higher th an that for LNs (P = 0.01). Unlike the changes in layer V, this latter change in layer II showed no relationship to neuroleptic exposure. Th ere was a positive correlation between age and the density of TH-IR va ricosities on SNs of layer II in ACCx; however, the patients were youn ger than the controls and would have been expected to show a lower den sity, rather than a higher one, if age considerations had accounted fo r the group differences. Overall, the results reported here suggest th at there are no gross differences in the distribution of TH-IR varicos ities in various laminae of the dorsolateral prefrontal cortex. In the anterior cingulate region, however, there may be a significant shift in the distribution of TH-IR varicosities from large neurons to small neurons that occurs selectively in layer II of schizophrenic subjects. Using size criteria, the majority of small neurons are likely nonpyra midal, while the majority of large neurons are predominantly pyramidal in nature. Taken together with other accumulating evidence of prefere ntial abnormalities in this lamina of the cingulate region, the findin gs reported here are consistent with a model of schizophrenia in which a subtle ''miswiring'' of ventral tegmental inputs may result in a re lative, though not absolute, hyperdopaminergic state with respect to a n impaired population of GABAergic interneurons. (C) 1997 Wiley-Liss, Inc.