Glutamatergic transmission in schizophrenia: From basic research to clinical practice
ABSTRACT Purpose of review: The past 20 years have seen the glutamatergic hypothesis go from theory to phase III trials of novel mechanism antipsychotics. Recent Findings: We review the recent literature on glutamatergic theory, covering assessment and genetic studies, as well as drug development in animals and humans. Summary: Although evidence continues to accumulate in support of glutamate hypotheses, further research continues to be required and interactions with other key systems need to be explored.
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ABSTRACT: Frequency specific synchronization of neuronal firing within the gamma-band (30-70Hz) appears to be a fundamental correlate of both basic sensory and higher cognitive processing. In-vitro studies suggest that the neurochemical basis of gamma-band oscillatory activity is based on interactions between excitatory (i.e. glutamate) and inhibitory (i.e. GABA) neurotransmitter concentrations. However, the nature of the relationship between excitatory neurotransmitter concentration and changes in gamma band activity in humans remains undetermined. Here, we examine the links between dynamic glutamate concentration and the formation of functional gamma-band oscillatory networks. Using concurrently acquired event-related magnetic resonance spectroscopy and electroencephalography, during a repetition-priming paradigm, we demonstrate an interaction between stimulus type (object vs. abstract pictures) and repetition in evoked gamma-band oscillatory activity, and find that glutamate levels within the lateral occipital cortex, differ in response to these distinct stimulus categories. Importantly, we show that dynamic glutamate levels are related to the amplitude of stimulus evoked gamma-band (but not to beta, alpha or theta or ERP) activity. These results highlight the specific connection between excitatory neurotransmitter concentration and amplitude of oscillatory response, providing a novel insight into the relationship between the neurochemical and neurophysiological processes underlying cognition.NeuroImage 07/2013; 85. DOI:10.1016/j.neuroimage.2013.07.049 · 6.13 Impact Factor
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ABSTRACT: Distinct frequency bands can be differentiated from neuronal ensemble recordings, such as local field potentials or electrocorticogram recordings. Recent years have witnessed a rapid acceleration of research examining how N-methyl-D-aspartate receptor (NMDAR) antagonists influence fundamental frequency bands in cortical and subcortical brain regions. Herein, we systematically review findings from in vivo studies with a focus on delta, theta, gamma and more recently identified high-frequency oscillations. We also discuss some of the current hypotheses that are considered to account for the actions of NMDAR antagonists on these frequency bands. The data emphasize a close relationship between altered oscillatory activity and NMDAR blockade, with both local and large-scale networks accounting for their effects. These findings may have fundamental implications for the psychotomimetic effects produced by NMDAR antagonists.Journal of Psychopharmacology 07/2013; 27(11). DOI:10.1177/0269881113495117 · 2.81 Impact Factor
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ABSTRACT: Cognitive deficits in individuals with schizophrenia (SCZ) are considered core symptoms of this disorder, and can manifest at the prodromal stage. Antipsychotics ameliorate positive symptoms but only modestly improve cognitive symptoms. The lack of treatments that improve cognitive abilities currently represents a major obstacle in developing more effective therapeutic strategies for this debilitating disorder. While D4 receptor (D4R)-specific antagonists are ineffective in the treatment of positive symptoms, animal studies suggest that D4R drugs can improve cognitive deficits. Moreover, recent work from our group suggests that D4Rs synergize with the neuregulin/ErbB4 signaling pathway, genetically identified as risk factors for SCZ, in parvalbumin (PV)-expressing interneurons to modulate gamma oscillations. These high-frequency network oscillations correlate with attention and increase during cognitive tasks in healthy subjects, and this correlation is attenuated in affected individuals. This finding, along with other observations indicating impaired GABAergic function, has led to the idea that abnormal neural activity in the prefrontal cortex (PFC) in individuals with SCZ reflects a perturbation in the balance of excitation and inhibition. Here we review the current state of knowledge of D4R functions in the PFC and hippocampus, two major brain areas implicated in SCZ. Special emphasis is given to studies focusing on the potential role of D4Rs in modulating GABAergic transmission and to an emerging concept of a close synergistic relationship between dopamine/D4R and neuregulin/ErbB4 signaling pathways that tunes the activity of PV interneurons to regulate gamma frequency network oscillations and potentially cognitive processes.Frontiers in Cellular Neuroscience 07/2013; 7:102. DOI:10.3389/fncel.2013.00102 · 4.18 Impact Factor