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Cited by 1,870Schizophrenia research and treatmentMental Health and PsychiatryNeurotransmitter Receptor Influence on Behavior

The DOI matches its Crossref record; 141 of the 141 references it cites were found in a registry or an index.

Schizophrenia

Open access
Owen, Michael J, Sawa, Akira, Mortensen, Preben B·2016·The Lancet
DOI 10.1016/s0140-6736(15)01121-6PMC PMC4940219
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Abstract

Schizophrenia is a complex, heterogeneous behavioural and cognitive syndrome that seems to originate from disruption of brain development caused by genetic or environmental factors, or both. Dysfunction of dopaminergic neurotransmission contributes to the genesis of psychotic symptoms, but evidence also points to a widespread and variable involvement of other brain areas and circuits. Disturbances of synaptic function might underlie abnormalities of neuronal connectivity that possibly involves interneurons, but the precise nature, location, and timing of these events are uncertain. At present, treatment mainly consists of antipsychotic drugs combined with psychological therapies, social support, and rehabilitation, but a pressing need for more effective treatments and delivery of services exists. Advances in genomics, epidemiology, and neuroscience have led to great progress in understanding the disorder, and the opportunities for further scientific breakthrough are numerous--but so are the challenges.

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Figure 1 The allelic spectrum of schizophrenia The figure depicts risk alleles for schizophrenia that have been robustly identified by genomic studies. The x-axis is the allele frequency (AF) in controls and the the y-axis is the odds ratio (genotypic relative risk). For clarity, confidence intervals are not shown. Copy number variants associated with schizophrenia are shown as blue diamonds. Single nucleotide polymorphism that are associated with SCZ and are shown as red diamonds. Alleles that confer high individual risk are rare in the population due to the effects of natural selection, whereas those conferring small effects on individual risk can become common due to genetic drift or balancing selection.
Figure 1 The allelic spectrum of schizophrenia The figure depicts risk alleles for schizophrenia that have been robustly identified by genomic studies. The x-axis is the allele frequency (AF) in controls and the the y-axis is the odds ratio (genotypic relative risk). For clarity, confidence intervals are not shown. Copy number variants associated with schizophrenia are shown as blue diamonds. Single nucleotide polymorphism that are associated with SCZ and are shown as red diamonds. Alleles that confer high individual risk are rare in the population due to the effects of natural selection, whereas those conferring small effects on individual risk can become common due to genetic drift or balancing selection.CC BY-NC-ND · PubMed Central
Figure 2 Representative molecular pathway for schizophrenia: fine tuning of the glutamate synapse Recent advances in human genetics, from both GWAS and large-scale sequencing, have further supported the significance of fine-tuning of glutamatergic neurotransmission in the pathology of schizophrenia. The genes underscored by these studies include those encoding the glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A); glutamate receptor ionotropic, AMPA 1 (GRIA1); serine racemase (SRR); calcium channel, voltage-dependent (VDCC), L type, alpha 1C subunit; the ARC complex, and a number of proteins located in, or associated with, the postsynaptic density of glutamatergic synapses. The N-methyl D-aspartate (NMDA)-type glutamate receptors are fine tuned by a co-agonist D-serine, which is synthesized by SRR. The GRIN2A subunit (in dark green) dimerizes with other type of subunit, forming the NMDA receptors, whereas the GRIA1 subunit (in brown) also forms heterodimers for the AMPA receptors. VDCCs (e.g., the protein encoded by the CACNA1C gene) are also likely to be involved in tuning neural excitability and synaptic transmission via intracellular calcium signaling. Proteins associated with postsynaptic scaffold include PSD95, Stargazin, several kinases, Rho/Cdc42/Rac small G-proteins, and ARC complex. In response to activation of glutamate receptors, these proteins convey intracellular signaling that underlies cytoskeletal regulation and receptor trafficking crucial for synaptic plasticity.
Figure 2 Representative molecular pathway for schizophrenia: fine tuning of the glutamate synapse Recent advances in human genetics, from both GWAS and large-scale sequencing, have further supported the significance of fine-tuning of glutamatergic neurotransmission in the pathology of schizophrenia. The genes underscored by these studies include those encoding the glutamate receptor, ionotropic, N-methyl D-aspartate 2A (GRIN2A); glutamate receptor ionotropic, AMPA 1 (GRIA1); serine racemase (SRR); calcium channel, voltage-dependent (VDCC), L type, alpha 1C subunit; the ARC complex, and a number of proteins located in, or associated with, the postsynaptic density of glutamatergic synapses. The N-methyl D-aspartate (NMDA)-type glutamate receptors are fine tuned by a co-agonist D-serine, which is synthesized by SRR. The GRIN2A subunit (in dark green) dimerizes with other type of subunit, forming the NMDA receptors, whereas the GRIA1 subunit (in brown) also forms heterodimers for the AMPA receptors. VDCCs (e.g., the protein encoded by the CACNA1C gene) are also likely to be involved in tuning neural excitability and synaptic transmission via intracellular calcium signaling. Proteins associated with postsynaptic scaffold include PSD95, Stargazin, several kinases, Rho/Cdc42/Rac small G-proteins, and ARC complex. In response to activation of glutamate receptors, these proteins convey intracellular signaling that underlies cytoskeletal regulation and receptor trafficking crucial for synaptic plasticity.CC BY-NC-ND · PubMed Central
Figure 3 Interaction of genetic and environmental risk factors in the developmental pathology of schizophrenia This shows a schematic view of how multiple genetic and environmental risk factors might impact on long-term neurodevelopmental processes leading to schizophrenia. Schizophrenia typically presents when the first episode of psychosis occurs in late adolescence or early adulthood but is frequently preceded by a prodromal phase and in some instances premorbid impairments in cognition and/or social functioning go back many years. It is proposed that disturbances generated by susceptibility genes (indicated by blue stars) and environmental insults (indicated by pink asterisks) during early development and adolescence disturb postnatal brain maturation. These factors are likely to impair some of the crucial processes in early development, including progenitor cell proliferation, neuronal migration and dendritic arborization and outgrowth. Independent of such initial risks/insults, intrinsic disease-associated factors might also directly affect postnatal brain maturation. Accumulation of such deleterious insults results in overall disturbance of proper postnatal brain maturation, including maturation of interneurons and dopaminergic projections, pruning of glutamate synapses and myelination. Therefore, it is crucial to understand the mechanisms that underlie long-term progression to full disease manifestation in young adulthood to facilitate development of novel therapeutic strategies. This contrasts with classic drug discovery that simply modulates disturbed neurotransmission after full onset of the disease. In this figure, interneuron maturation is plotted as an increase in interneuron response to dopamine D2 agonists in the prefrontal cortex, whereas mesocortical dopaminergic projection is based on levels of tyrosine hydroxylase. The relative levels of glutamatergic synapse density and myelination are depicted. Extensively modified from the original figure appeared in Jaaro-Peled et al, TINS 2009.
Figure 3 Interaction of genetic and environmental risk factors in the developmental pathology of schizophrenia This shows a schematic view of how multiple genetic and environmental risk factors might impact on long-term neurodevelopmental processes leading to schizophrenia. Schizophrenia typically presents when the first episode of psychosis occurs in late adolescence or early adulthood but is frequently preceded by a prodromal phase and in some instances premorbid impairments in cognition and/or social functioning go back many years. It is proposed that disturbances generated by susceptibility genes (indicated by blue stars) and environmental insults (indicated by pink asterisks) during early development and adolescence disturb postnatal brain maturation. These factors are likely to impair some of the crucial processes in early development, including progenitor cell proliferation, neuronal migration and dendritic arborization and outgrowth. Independent of such initial risks/insults, intrinsic disease-associated factors might also directly affect postnatal brain maturation. Accumulation of such deleterious insults results in overall disturbance of proper postnatal brain maturation, including maturation of interneurons and dopaminergic projections, pruning of glutamate synapses and myelination. Therefore, it is crucial to understand the mechanisms that underlie long-term progression to full disease manifestation in young adulthood to facilitate development of novel therapeutic strategies. This contrasts with classic drug discovery that simply modulates disturbed neurotransmission after full onset of the disease. In this figure, interneuron maturation is plotted as an increase in interneuron response to dopamine D2 agonists in the prefrontal cortex, whereas mesocortical dopaminergic projection is based on levels of tyrosine hydroxylase. The relative levels of glutamatergic synapse density and myelination are depicted. Extensively modified from the original figure appeared in Jaaro-Peled et al, TINS 2009.CC BY-NC-ND · PubMed Central
Figure 4 Neuron-glia interactions in the cerebral cortex: key neural substrates for the pathology of schizophrenia In the cerebral cortex, interneurons (inhibitory neurons) regulate the output of pyramidal neurons (excitatory neurons). Many studies have reported abnormalities of interneurons (in particular parvalbumin-positive interneurons) and deficits of dendritic spines in the pyramidal neurons in the pathology of schizophrenia. Imbalance of excitatory and inhibitory neurons may be a key feature that underlies the pathology. Recent neurobiology indicates that astrocytes and microglia play key a role in maintenance and pruning of the dendritic spines, in association with immune inflammatory response in the brain. Oligodendrocytes create the myelin sheath, which is crucial for signal transmission inside the axon. Abnormalities of these glial cells have also been reported in schizophrenia.
Figure 4 Neuron-glia interactions in the cerebral cortex: key neural substrates for the pathology of schizophrenia In the cerebral cortex, interneurons (inhibitory neurons) regulate the output of pyramidal neurons (excitatory neurons). Many studies have reported abnormalities of interneurons (in particular parvalbumin-positive interneurons) and deficits of dendritic spines in the pyramidal neurons in the pathology of schizophrenia. Imbalance of excitatory and inhibitory neurons may be a key feature that underlies the pathology. Recent neurobiology indicates that astrocytes and microglia play key a role in maintenance and pruning of the dendritic spines, in association with immune inflammatory response in the brain. Oligodendrocytes create the myelin sheath, which is crucial for signal transmission inside the axon. Abnormalities of these glial cells have also been reported in schizophrenia.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Owen, M. J., Sawa, A., & Mortensen, P. B.
Affiliations
  • Cardiff University (GB)
  • Johns Hopkins University (US)
  • Aarhus University (DK)
Corresponding author
Owen, Michael J
ORCID
Venue
The Lancet
Publisher
Elsevier BV
Published
2016-07
Volume
388
Issue
10039
Pages
86-97
ISSN
  • 0099-5355 (ISSN-L)
  • 0140-6736
DOI
10.1016/s0140-6736(15)01121-6
PMC
PMC4940219
OpenAlex
W4211145950
Cited by
1,870
References
141
Citations by year
2026: 182 · 2025: 188 · 2024: 214 · 2023: 198 · 2022: 259 · 2021: 226 · 2020: 173 · 2019: 143 · 2018: 152 · 2017: 97 · 2016: 37
FWCI
20.55
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
Funders
  • Wellcome Trust
  • Lundbeckfonden (R155-2014-1724)
  • Medical Research Council (MR/L010305/1)
  • National Institute of Mental Health (R21MH085226, MH‐105660, MH084018, MH085226, RC1MH088753, MH 092443, MH‑088753, P20MH084018, R01MH069853, R01MH105660, MH-094268, P50MH094268, MH069853, R01MH092443)
  • National Institute on Drug Abuse (DA-040127, R21DA040127)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
schizophrenia, brain development, genetic factors, environmental factors, dopamine signaling, psychotic symptoms, synaptic dysfunction, neuronal connectivity, interneurons, antipsychotic drugs, psychotherapy, social support, rehabilitation, genomics
MeSH terms
Brain, Cognition Disorders, Environmental Exposure, Humans, Psychotherapy, Schizophrenia, Schizophrenic Psychology, Social Support, Social Work, Antipsychotic Agents

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