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: The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis.Frontiers in Cellular Neuroscience 01/2013; 7:60. · 4.47 Impact Factor
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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:e215.
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ABSTRACT: Individuals with schizophrenia display a number of structural and cytoarchitectural alterations in the hippocampus, suggesting that other functions such as synaptic plasticity may also be modified. Altered hippocampal plasticity is likely to affect memory processing, and therefore any such pathology may contribute to the cognitive symptoms of schizophrenia, which includes prominent memory impairment. The current study tested whether prenatal exposure to infection, an environmental risk factor that has previously been associated with schizophrenia produced changes in hippocampal synaptic transmission or plasticity, using the maternal immune activation (MIA) animal model. We also assessed performance in hippocampus-dependent memory tasks to determine whether altered plasticity is associated with memory dysfunction. MIA did not alter basal synaptic transmission in either the dentate gyrus or CA1 of freely-moving adult rats. It did, however, result in increased paired-pulse facilitation of the dentate gyrus population spike and an enhanced persistence of dentate long-term potentiation. MIA animals displayed slower learning of a reversed platform location in the water maze, and a similarly slowed learning during reversal in a spatial plus maze task. Together these findings are indicative of reduced behavioral flexibility in response to changes in task requirements. The results are consistent with the hypothesis that hippocampal plasticity is altered in schizophrenia, and that this change in plasticity mechanisms may underlie some aspects of cognitive dysfunction in this disorder. © 2013 Wiley Periodicals, Inc.Hippocampus 08/2013; · 5.49 Impact Factor