Reynolds GP, Beasley CL, Zhang ZJ. Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons. J Neural Transm 109: 881-889

Department of Biomedical Science, University of Sheffield, Sheffield, United Kingdom.
Journal of Neural Transmission (Impact Factor: 2.4). 06/2002; 109(5-6):881-9. DOI: 10.1007/s007020200072
Source: PubMed


Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.

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    • "Schizophrenia is a disease affecting up to 1% of the population.1 Whereas the exact etiology of schizophrenia is not currently known, an alteration in GABAergic function is a consistent observation in both animal models as well as post-mortem studies in schizophrenia patients.2, 3, 4, 5, 6, 7, 8 Specifically, post-mortem studies have demonstrated a reduction in cortical glutamic acid decarboxylase;9, 10, 11 an upregulation of post-synaptic GABA-A receptors12, 13 and a decrease in GABA uptake sites14, 15, 16 in schizophrenia patients. There is increasing evidence that deficits in GABAergic transmission are demonstrated to occur within specific classes of GABAergic interneurons, with considerable attention being paid to those containing the calcium binding protein parvalbumin.3 "
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    ABSTRACT: Deficits in parvalbumin containing interneurons are a consistent observation in animal models and schizophrenia patients. These neurons are surrounded by chondroitin sulfate proteoglycans, forming perineuronal nets, thought to support the high firing frequencies observed in these neurons. A loss of perineuronal nets has been observed post mortem in human schizophrenia patients, however, whether this contributes to the symptoms of schizophrenia is not known. Here we directly examine the effects of chondroitinase ABC degradation of ventral hippocampal (vHipp) perineuronal nets, and demonstrate that this results in an enhanced hippocampal activity and significant increase in dopamine neuron population activity. In addition, chondroitinase-treated rats display an augmented locomotor response to amphetamine, consistent with the enhanced response to psychomotor stimulants observed in schizophrenia patients. Taken together, these data demonstrate that a loss of vHipp perineuronal nets is sufficient, in and of itself, to induce aberrant hippocampal and dopamine system function consistent with that observed in rodent models and schizophrenia patients.
    Translational Psychiatry 01/2013; 3(1):e215. DOI:10.1038/tp.2012.145 · 5.62 Impact Factor
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    • "Loss of TH-IR neurons in the human cortex was noted in dementia (Marui et al., 2003) and Parkinson's disease (Fukuda et al., 1999). Furthermore, aberrant interneuron development has been linked to several major neurological disorders, including epilepsy, schizophrenia, bipolar disorder, and depression (Benes and Berretta, 2001; Reynolds et al., 2002; Powell et al., 2003; Levitt et al., 2004; Lewis et al., 2005; Garbelli et al., 2006; Daskalakis et al., 2007; Di Cristo, 2007; Rajkowska et al., 2007; Gonzalez-Burgos and Lewis, 2008; Barinka et al., 2010). Further characterization of the subpopulation of cortical interneurons that produces TH will provide insight into the functions of these cells across species and is warranted because of their potential clinical relevance. "
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    ABSTRACT: Cortical interneurons are critical for information processing, and their dysfunction has been implicated in neurological disorders. One subset of this diverse cell population expresses tyrosine hydroxylase (TH) during postnatal rat development. Cortical TH-immunoreactive neurons appear at postnatal day (P) 16. The number of TH cells sharply increases between P16 and P20 and subsequently decreases to adult values. The absence of apoptotic markers in these cells suggests that the reduction in cell number is not due to cell death but is due to a decline in TH production. Cortical TH cells lack all additional catecholaminergic enzymes, and many coexpress GABA and calretinin, but little else is known about their phenotype or function. Because interneurons containing choline acetyltransferase (ChAT) or vasoactive intestinal peptide (VIP) share characteristics with cortical TH neurons, the coexpression of TH with ChAT or VIP was examined throughout the neocortex at P16, P20, and P30. The proportions of TH cell profiles double-labeled for ChAT or VIP significantly increased between P16 and P30. Based on their proximity to blood vessels, intrinsic cholinergic and VIPergic cells have been hypothesized to regulate cortical microcirculation. Labeling with the gliovascular marker aquaporin-4 revealed that at least half of the TH cells were apposed to microvessels at these ages, and many of these cells contained ChAT or VIP. Cortical TH neurons did not coproduce nitric oxide synthase. These results suggest that increasing proportions of cortical TH neurons express ChAT or VIP developmentally and that a subset of these TH neurons may regulate local blood flow.
    Brain research 02/2011; 1383:108-19. DOI:10.1016/j.brainres.2011.01.101 · 2.84 Impact Factor
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    • "Recent studies indicate that the power of gamma oscillations in subjects diagnosed with schizophrenia is reduced (Kwon et al. 1999; Wilson et al. 2007), and that regional reaction time phase-lock of oscillations is correlated with either the positive or negative symptoms of the disorder (Spencer et al. 2004). In addition, the amounts of RNA and immunoreactivity for parvalbumin (PV) are reduced in post-mortem tissue from the frontal cortex and the hippocampus of schizophrenic patients (Reynolds et al. 2002; Zhang and Reynolds 2002; Hashimoto et al. 2003; Torrey et al. 2005), and a direct relation to the changes in gamma oscillations has been suggested (Lewis et al. 2005). Neuregulin-1 (NRG-1) is a trophic and differentiation factor that signals via ErbB receptor tyrosine kinases (ErbB2--ErbB4) and that harbors an epidermal growth factor (EGF)–like domain mediating its biological effects (Buonanno and Fischbach 2001). "
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    ABSTRACT: Alterations in gamma-frequency oscillations are implicated in psychiatric disorders, and polymorphisms in NRG-1 and ERBB4, genes encoding Neuregulin-1 (NRG-1) and one of its receptors, designated ErbB4, are associated with schizophrenia. Here we show that NRG-1 selectively increases the power of kainate-induced, but not carbachol-induced, gamma oscillations in acute hippocampal slices. NRG-1beta is more effective than NRG-1alpha, a splice variant with lower affinity for ErbB receptors, and neither isoform affects the network activity without prior induction of gamma oscillations. NRG-1beta dramatically increases gamma oscillation power in hippocampal slices from both rats (2062 +/- 496%) and mice (710 +/- 299%). These effects of NRG-1beta are blocked by PD158780, a pan-specific antagonist of ErbB receptors, and are mediated specifically via ErbB4 receptors, because mice harboring a targeted mutation of ErbB4 do not respond to NRG-1. Moreover, we demonstrate that 50% of gamma-amino butyric acidergic parvalbumin (PV)-positive interneurons, which heavily contribute to the generation of gamma oscillations, express ErbB4 receptors. Importantly, both the number of PV-immunoreactive interneurons (-31%) and the power of kainate-induced gamma oscillations (-60%) are reduced in ErbB4 knockout mice. This study provides the first plausible link between NRG-1/ErbB4 signaling and rhythmic network activity that may be altered in persons with schizophrenia.
    Cerebral Cortex 03/2009; 19(3):612-8. DOI:10.1093/cercor/bhn107 · 8.67 Impact Factor
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