Somal Size of Prefrontal Cortical Pyramidal Neurons in Schizophrenia: Differential Effects across Neuronal Subpopulations Joseph N. Pierri, Christine L.E. Volk, Sungyoung Auh, Allan Sampson, and David A. Lewis Background: Cognitive dysfunction in schizophrenia may be related to morphologic abnormalities of pyramidal neurons in the dorsal prefrontal cortex (dPFC) and the largest pyramidal neurons in deep layer 3 may be most affected. Immunoreactivity (IR) for the nonphosphorylated epitopes of neurofilament protein (NNFP) identifies a subset of large dPFC deep layer 3 pyramidal neurons. We tested the hypotheses that the average size of NNFP-IR neurons is smaller in schizophrenia and that the decrease in size of these neurons is greater than that observed in the general population of deep layer 3 pyramidal neurons. Methods: We estimated the mean somal volume of NNFP-IR neurons in deep layer 3 of 9 in 13 matched pairs of control and schizophrenia subjects and compared the differences in somal size of NNFP-IR neurons to the differences in size of all deep layer 3 pyramidal neurons identified in Nissl-stained material. Results: In subjects with schizophrenia, the somal volume of NNFP-IR neurons was nonsignificantly decreased by 6.6%, whereas that of the Nissl-stained pyramidal neurons was significantly decreased by 14.2%. Conclusions: These results suggest that the NNFP-IR subpopulation of dPFC pyramidal neurons are not pref- erentially affected in schizophrenia. Thus, a subpopula- tion of dPFC deep layer 3 pyramidal neurons, other than those identified by NNFP-IR, may be selectively vulnerable in schizophrenia. Biol Psychiatry 2003;54: 111–120 © 2003 Society of Biological Psychiatry Key Words: Schizophrenia, postmortem, prefrontal cor- tex, pyramidal neurons, somal size, neurofilament protein Introduction O n average, subjects with schizophrenia perform worse than healthy control subjects on tests of cognitive abilities subserved by the dorsolateral prefrontal cortex (dPFC; Park and Holzman 1992; Steinberg et al 1996; Weinberger et al 1986). Recent evidence suggests that this cognitive dysfunction may be related to abnormalities in pyramidal neurons located in deep layer 3 of the dPFC. Specifically, dPFC deep layer 3 pyramidal neurons have been reported to have smaller cell bodies (Pierri et al 2001; Rajkowska et al 1998), shorter dendrites (Garey et al 1998; Glantz and Lewis 2000), and fewer dendritic spines in subjects with schizophrenia (Garey et al 1998; Glantz and Lewis 2000). One study suggested that the largest cells in deep layer 3, most likely pyramidal neurons, showed the greatest decrements in density; thus, these neurons were hypothesized to be particularly vulnerable in schizophre- nia (Rajkowska et al 1998). The functional integrity of a population of neurons may be reflected in estimates of their average cell body size. For example, changes in somal size may indicate distur- bances in neuronal connectivity, given that somal size has been shown to be correlated with measures of a neuron’s dendritic (Hayes and Lewis 1993; Jacobs et al 1997) and axonal architecture (Gilbert and Kelly 1975; Lund et al 1975). Indeed, we reported that the average somal size of dPFC deep layer 3 pyramidal neurons was reduced in subjects with schizophrenia and that the size of these neurons was correlated with average total dendritic length, even across two labeling procedures (Pierri et al 2001). These findings suggest that somal size may provide clues as to abnormalities in neuronal connectivity, an anatomic feature that is difficult to assess directly in the postmortem state. Pyramidal neurons in deep layer 3 of the dPFC are heterogeneous with respect to the targets of their axon projections (DeFelipe and Farinas 1992), and distinct populations of dPFC deep layer 3 pyramidal neurons project to various cortical regions (Soloway et al 2002). From the Departments of Psychiatry (JNP, CLEV, DAL), Neuroscience (DAL), and Statistics (SA, AS), University of Pittsburgh, Pittsburgh, Pennsylvania. Address reprint requests to David A. Lewis, M.D., University of Pittsburgh, 3811 O’Hara Street, W1650 BST, Pittsburgh PA 15213. Received October 29, 2002; revised March 12, 2003; accepted March 14, 2003. © 2003 Society of Biological Psychiatry 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00294-4