The regulated expression of neural cell adhesion molecule (NCAM) isoforms in the brain is critical for many neurodevelopmental processes including neurulation, axonal outgrowth, and the establishment of neuronal connectivity. We have investigated the expression of the major adult isoforms of NCAM and its embryonic highly polysialylated isoform (PSA-NCAM) in the hippocampal region of postmortem brains from 10 schizophrenic and 11 control individuals. Immunohistochemical analysis with a monoclonal antibody recognizing the PSA-NCAM revealed immunoreactivity primarily in the dentate gyrus and in a subset of cells in the hilus region. We have observed a 20-95% reduction in the number of hilar PSA-NCAM-immunoreactive cells in the great majority of schizophrenic brains. The change in PSA-NCAM immunoreactivity is not obvious in other hippocampal subfields. Western blots of tissues from the hippocampal region (as well as from the frontal cortex) probed with a polyclonal antibody recognizing all NCAM isoforms did not reveal significant changes in the overall expression of NCAM, suggesting that the decrease in PSA-NCAM-immunoreactive cells may be related to posttranslational processing of the molecule. The expression of this embryonic form of NCAM has been proposed to be related to synaptic rearrangement and plasticity. Therefore, the decrease in PSA-NCAM immunoreactivity in schizophrenic hippocampi may suggest an altered plasticity of this structure in a large proportion of schizophrenic brains. These findings may bear significance to the "neurodevelopmental hypothesis" of schizophrenia.

Functional and structural abnormalities in the medial prefrontal cortex (MPFC) and overactive dopamine (DA) neurotransmission are thought to be the key pathologies in schizophrenia. To understand the role of MPFC in the pre- and postpubertal development of the subcortical DA system, the effects of neonatal [postnatal day 7 (PD7)] MPFC excitotoxic lesions on locomotor behaviors and the expression of DA receptor subtypes and DA transporter were investigated in Sprague Dawley rats at PD35 and PD56, respectively. No significant differences in the novelty of d-amphetamine-induced locomotion were observed between sham-operated and ibotenic acid-lesioned rats at PD35. Postpubertally (at PD56), however, the locomotor activity of lesioned rats in the novel environment and after d-amphetamine administration was enhanced significantly compared with controls. The expressions of DA D1, D2, D3, and D4 receptors and DA transporter were then estimated in MPFC-lesioned and sham-operated rats at PD59 and PD60. The levels of DA D2 receptors, measured using [3H]-YM-09151-2 binding, and its mRNA by in situ hybridization, were observed to be significantly increased at PD60 in striatal and limbic areas of lesioned rats. Levels of other DA receptor subtypes were not significantly affected at any time points. Lesioned rats at PD39 show a small increase in DA transporter level in the shell of nucleus accumbens; however, this effect seems to wear off at PD60. The data suggest that neonatal MPFC lesions may alter the functional development and maturation of mesolimbic/nigrostriatal DA systems in that neonatally lesioned rats grow into a behavioral/neurochemical deficit.

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Abstract:Regulators of G protein signaling (RGS) proteins serve as potent GTPase-activating proteins for the heterotrimeric G proteins ␣i/o and ␣q/11. This study describes the immunohistochemical distribution of RGS7 throughout the adult rat brain and its cellular colocalization with G␣q/11, an important G protein-coupled receptor signal transducer for phospholipase C␤-mediated activity. In general, both RGS7 and G␣q/11 displayed a heterogeneous and overlapping regional distribution. RGS7 immunoreactivity was observed in cortical layers I-VI, being most intense in the neuropil of layer I. In the hippocampal formation, RGS7 immunoreactivity was concentrated in the strata oriens, strata radiatum, mossy fibers, and polymorphic cells, with faint to nondetectable immunolabeling within the dentate gyrus granule cells and CA1-CA3 subfield pyramidal cells. Numerous diencephalic and brainstem nuclei also displayed dense RGS7 immunostaining. Dual immunofluorescence labeling studies with the two protein-specific antibodies indicated a cellular selectivity in the colocalization between RGS7 and G␣q/11 within many discrete brain regions, such as the superficial cortical layer I, hilus area of the hippocampal formation, and cerebellar Golgi cells. To assess the ability of G␣q/11-mediated signaling pathways to modulate dynamically RGS expression, primary cortical neuronal cultures were incubated with phorbol 12,13-dibutyrate, a selective protein kinase C activator. A time-dependent increase in levels of mRNA for RGS7, but not RGS4, was observed. Our results provide novel information on the region-and cell-specific pattern of distribution of RGS7 with the transmembrane signal transducer, G␣q/11. We also describe a possible RGS7-selective neuronal feedback adaptation on G␣q/11-mediated pathway function, which may play an important role in signaling specificity in the brain. Key Words: Regulator of G protein signaling 7-G␣q/11-Brain localization-Immunohistochemistry-Rat-Confocal microscopy. J. Neurochem. 72, 174 -184 (1999).Regulators of G protein signaling (RGS) proteins are GTPase-activating proteins for several G protein ␣-subunit members (G␣i and G␣q) and serve to attenuate G protein signaling (Koelle, 1997;Yan et al., 1997;Berman and Gilman, 1998;Shuey et al., 1998). Activation of G protein-coupled receptors catalyzes the exchange of G␣-bound GDP for GTP to cause the dissociation of G␣ from the G␤␥ dimer and initiate downstream signal propagation; RGS proteins terminate signaling by accelerating the relatively slow intrinsic G␣-GTPase activity and recycling the G protein complex back to its inactive GDP-bound heterotrimeric configuration (Dohlman and Thorner, 1997;Koelle, 1997;Neer, 1997).Of 19 mammalian genes that express mRNAs with a conserved RGS core domain, many of these demonstrate regional specificity and heterogeneous expression within the rat CNS (Gold et al., 1997;Shuey et al., 1998). Both RGS4 and RGS7 mRNAs are prevalent in brain Koelle and Horvitz, 1996;Gold et al., 1997;Shuey et al., 1998) and have become the f...

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