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Schizophrenia: Basic and Clinical

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Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 15))

Abstract

Schizophrenia is a chronic severe mental disorder characterized by psychosis, cognitive impairments, and social and motivational deficits. It is associated with a progressive loss of cortical volume after onset of psychosis; nevertheless, cortical atrophy correlates with the cognitive impairments and the negative symptoms but not with the psychosis. The cortical atrophy is not primarily due to neuronal degeneration but rather to neuronal atrophy and loss of glutamatergic synapses. A downregulation of the presynaptic markers for the parvalbumin-expressing GABAergic interneurons that provide recurrent inhibition to cortical pyramidal neurons is another consistent pathologic feature. Antipsychotic drugs continue after 50 years to be the mainstay of treatment although these drugs, with the possible exception of clozapine, have negligible effects on cognition and negative symptoms. Pharmacologic challenge studies, postmortem analyses and a recent sufficiently powered genome-wide association study and copy number variant studies provide compelling evidence that NMDA receptor hypofunction is an important pathophsysiologic feature of schizophrenia. Silencing the gene encoding serine racemase, the enzyme that synthesizes the cortical-limbic NMDA receptor co-agonist, d-serine, replicates the dendritic and GABAergic pathology and cognitive deficits of schizophrenia in mice. Pharmacologic strategies to overcome NMDA receptor hypofunction hold promise of treating the disabling cognitive and negative symptoms.

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Abbreviations

Akt1:

Alpha serine/threonine-protein kinase

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

Arc:

Activity-regulated cytoskeleton-associated protein

CAT:

Computer assisted tomography

CLCN-3:

Chloride channel, voltage-sensitive 3

CNV:

Copy number variant

DLG1 or SAP97:

Synapse associated protein-97

DSM:

Diagnostic statistical manual

DTI:

Diffusion tensor imaging

FA:

Fractional anisotropy

FDA:

Federal Drug Administration

fMRI:

Functional magnetic imaging

GABA:

γ-Amino butyric acid

GAD:

Glutamic acid decarboxylase

GlyT1:

Glycine transporter-1

GMS:

Glycine modulatory site

GWAS:

Genome-wide association study

LTP:

Long-term potentiation

MEF2C:

Myocyte enhancer factor

mGluR3:

Metabotropic glutamate receptor-3

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

NMDA:

N-Methyl-d-aspartic acid

PCR:

Polymerase chain reaction

PSD-95:

Postsynaptic density-95

PV:

Parvalbumin

RDoC:

Research domain criteria

SNPs:

Single nucleotide polymorphisms

srr :

Serine racemase gene

TrkB:

Tropomyosin receptor kinase

VBR:

Ventricular brain ratio

VTA:

Ventral tegmental area

α-7-nAChR:

α-7-Nicotinic receptor

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Acknowledgments

The author reports consulting relationships with Forum Pharmaceuticals, Abbvie and Novartis in the past 3 years. His research has been supported by National Institutes of Health Grants R01MH05190 and P50MH0G0450. JTC reports having consulted with Forum Pharmaceutical, Novartis and Abbvie in the last 3 years and holds a patent on d-serine to treat serious mental disorders that is owned by the Massachusetts Hospital.

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The Author declares there is no conflict of interest.

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Coyle, J.T. (2017). Schizophrenia: Basic and Clinical. In: Beart, P., Robinson, M., Rattray, M., Maragakis, N. (eds) Neurodegenerative Diseases. Advances in Neurobiology, vol 15. Springer, Cham. https://doi.org/10.1007/978-3-319-57193-5_9

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