Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons.
ABSTRACT 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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ABSTRACT: Adolescent exposure to cannabinoids in vulnerable individuals is proposed to be a risk factor for psychiatric conditions later in life, particularly schizophrenia. Evidence from studies in animals has indicated that a combination of repeated pubertal cannabinoid administration with either neonatal prefrontocortical lesion, isolation rearing or chronic NMDA receptor antagonism administration induces enhanced schizophrenia-like behavioral disruptions. The effects of adolescent exposure to CB1 receptor agonists, however, have not been tested in a developmental disruption model of schizophrenia. This was tested in the methylazoxymethanol (MAM) model, in which repeated treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN; 1.2 mg/kg) was extended over 25 days throughout puberty (PD40-PD65) in control and MAM rats. The rats received 20 injections which were delivered irregularly to mimic the human condition. Adult rats were tested for attentional set-shifting task and locomotor response to amphetamine, which was compared with in vivo recording from ventral tegmental area (VTA) dopamine (DA) neurons. MAM-treated rats showed impairment in the attentional set-shifting task, augmented locomotor response to amphetamine administration and increased number of spontaneously active DA neurons in the VTA. Interestingly, pubertal WIN treatment in normal animals induced similar changes at adulthood as those observed in MAM-treated rats, supporting the notion that adolescence exposure to cannabinoids may represent a risk factor for developing schizophrenia-like signs at adulthood. However, contrary to expectations, pubertal WIN administration did not exacerbate the behavioral and electrophysiological changes in MAM-treated rats beyond that observed in WIN-treated saline rats. Indeed, WIN treatment actually attenuated the locomotor response to amphetamine in MAM rats without impacting DA neuron activity states. Taken together, the present results indicate that the impact of cannabinoids during puberty/adolescence on schizophrenia models is more complex than may be predicted. © The Author 2014. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 12/2014; · 5.26 Impact Factor
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ABSTRACT: Background: Schizophrenia is one of the most disabling psychiatric disorders, with serious consequences on families and society. Although a genetic component in its aetiology is indisputable, environmental factors also play an important role. Vitamin D (VD) has been implicated in central nervous system development and some evidence points to its role on schizophrenia aetiology. We aim to summarize brain alterations occurring in schizophrenia and how VD is relevant to them. Methods: Literature review up to 30th September 2014, using MeSH terms schizophrenia, vitamin D, brain, and central nervous system. Results: We summarize alterations occurring at anatomical and histological levels. Moreover, we describe biological pathways in which VD is involved that are proven to be disrupted in schizophrenia: neurotrophic factors, neurotransmission, synaptic and cytoskeleton anomalies, calcium homeostasis, energy metabolism and redox balance. Finally, we give some emphasis to cognitive disturbances. Conclusions: The heterogeneity of some studies does not allow to definitely affirm that VD deficit plays a role on schizophrenia aetiology. Studies on different populations and animal models should be conducted in order to achieve reproducible results. Therefore, this paper should be regarded as a guide to the pathways and anatomical structures disrupted by VD deficit in schizophrenia, and warrant further investigation. Although we cannot definitely affirm that VD deficiency is essential for schizophrenia aetiology, literature currently points to this hypothesis.International Journal of Clinical Neurosciences and Mental Health. 12/2014; 1(16):1-14.
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ABSTRACT: Neuregulin1 and its receptor ErbB4 are confirmed risk genes for schizophrenia, but the neuropathological alterations in NRG1-ErbB4 in schizophrenia are unclear. The present investigations therefore focused on determining lamina specific (ErbB4-pan) and quantitative (pan, JMa, JMb, CYT1 and CYT2) mRNA changes in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. We also determined which neuronal profiles are ErbB4 mRNA+ in the human DLPFC and the relationship between ErbB4 and interneuron marker mRNAs. In situ hybridisation and quantitative PCR measurements were performed to determine changes in ErbB4 splice variant mRNA levels in the DLPFC in schizophrenia (n=37) compared to control (n=37) subjects. Cortical neurons expressing ErbB4-pan were labelled with silver grain clusters. Correlations were performed between ErbB4 and interneuron mRNA levels. ErbB4-pan mRNA was significantly increased (layers I-II, V) in the DLPFC in schizophrenia. Silver grain clusters for ErbB4-pan were detected predominantly over small-medium neurons with low-no expression in the larger, paler, more triangular neuronal profiles. ErbB4-JMa mRNA expression was increased in schizophrenia. Somatostatin, neuropeptide Y and vasoactive intestinal peptide mRNAs negatively correlated with ErbB4-JMa mRNA in people with schizophrenia. Our findings demonstrate that ErbB4-pan laminar mRNA expression is elevated (layers I, II, V) in schizophrenia. At the cellular level, ErbB4-pan mRNA+ signal was detected predominantly in interneuron-like neurons. We provide evidence from this independent Australian post-mortem cohort that ErbB4-JMa expression is elevated in schizophrenia and is linked to deficits in dendrite-targeting somatostatin, neuropeptide Y and vasoactive intestinal peptide interneurons.Journal of Psychiatric Research 03/2014; In press. · 4.09 Impact Factor