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Cited by 345Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersTreatment of Major Depression

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Synapse Pathology in Psychiatric and Neurologic Disease

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van Spronsen, Myrrhe, Hoogenraad, Casper C.·2010·Current Neurology and Neuroscience Reports
DOI 10.1007/s11910-010-0104-8PMC PMC2857788
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Abstract

Inhibitory and excitatory synapses play a fundamental role in information processing in the brain. Excitatory synapses usually are situated on dendritic spines, small membrane protrusions that harbor glutamate receptors and postsynaptic density components and help transmit electrical signals. In recent years, it has become evident that spine morphology is intimately linked to synapse function--smaller spines have smaller synapses and support reduced synaptic transmission. The relationship between synaptic signaling, spine shape, and brain function is never more apparent than when the brain becomes dysfunctional. Many psychiatric and neurologic disorders, ranging from mental retardation and autism to Alzheimer's disease and addiction, are accompanied by alterations in spine morphology and synapse number. In this review, we highlight the structure and molecular organization of synapses and discuss functional effects of synapse pathology in brain disease.

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Fig. 1 Molecular architecture of inhibitory and excitatory synapses. The top panels show excitatory and inhibitory synapses. Excitatory synapses target on mature mushroom-shaped spines containing a prominent postsynaptic density (PSD), and inhibitory synapses are present along the dendritic shaft lacking postsynaptic thickening. Various organelles support the synapse; mitochondria provide energy, polyribosomes and RNA particles allow local protein synthesis, recycling endosomes (REs) transport internalized synaptic receptors back to the plasma membrane, and the cytoskeleton regulates spine dynamics. The abundant actin cytoskeleton is connected to the PSD and is the primary determinant of spine shape and motility. Transient invasion of dynamic microtubule into dendritic spines can regulate formation of spine head protrusions and rapid spine growth. Excitatory and inhibitory synapses contain a unique set of channels, scaffolding proteins, and other postsynaptic molecules. The microanatomy of the inhibitory and excitatory synapses and their organization of proteins and protein–protein interactions are depicted in the left and right panels, respectively. Major families of postsynaptic proteins are shown, including scaffolding proteins, adhesion molecules, and receptors. The lower panel shows major morphologic events occurring in dendritic spines upon long-term potentiation (LTP; left) or long-term depression (LTD; right). In Alzheimer’s disease and mental retardation, signaling cascades are triggered similar to LTD, leading to thinner, immature spines. In contrast, cocaine addiction shows similarities to LTP, resulting in bigger, mushroom-shaped, mature spines. The molecular and morphologic changes in the synapse are hallmarks of the disease pathology and are responsible for the cognitive alterations in neuropsychiatric diseases. CamKII—Ca2+/calmodulin-dependent kinase II; AMPAR—amino-3-hydroxy-5-methyl-4-isoazolepropionate receptor; GABA—γ-aminobutyric acid; GABAR—GABA receptor; NMDAR—N-methyl-d-aspartate receptor; mGluR—metabotropic glutamate receptor; SAPAP—synapse-associated protein 90/PSD-95-associated protein
Fig. 1 Molecular architecture of inhibitory and excitatory synapses. The top panels show excitatory and inhibitory synapses. Excitatory synapses target on mature mushroom-shaped spines containing a prominent postsynaptic density (PSD), and inhibitory synapses are present along the dendritic shaft lacking postsynaptic thickening. Various organelles support the synapse; mitochondria provide energy, polyribosomes and RNA particles allow local protein synthesis, recycling endosomes (REs) transport internalized synaptic receptors back to the plasma membrane, and the cytoskeleton regulates spine dynamics. The abundant actin cytoskeleton is connected to the PSD and is the primary determinant of spine shape and motility. Transient invasion of dynamic microtubule into dendritic spines can regulate formation of spine head protrusions and rapid spine growth. Excitatory and inhibitory synapses contain a unique set of channels, scaffolding proteins, and other postsynaptic molecules. The microanatomy of the inhibitory and excitatory synapses and their organization of proteins and protein–protein interactions are depicted in the left and right panels, respectively. Major families of postsynaptic proteins are shown, including scaffolding proteins, adhesion molecules, and receptors. The lower panel shows major morphologic events occurring in dendritic spines upon long-term potentiation (LTP; left) or long-term depression (LTD; right). In Alzheimer’s disease and mental retardation, signaling cascades are triggered similar to LTD, leading to thinner, immature spines. In contrast, cocaine addiction shows similarities to LTP, resulting in bigger, mushroom-shaped, mature spines. The molecular and morphologic changes in the synapse are hallmarks of the disease pathology and are responsible for the cognitive alterations in neuropsychiatric diseases. CamKII—Ca2+/calmodulin-dependent kinase II; AMPAR—amino-3-hydroxy-5-methyl-4-isoazolepropionate receptor; GABA—γ-aminobutyric acid; GABAR—GABA receptor; NMDAR—N-methyl-d-aspartate receptor; mGluR—metabotropic glutamate receptor; SAPAP—synapse-associated protein 90/PSD-95-associated proteinCC BY-NC · PubMed Central

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Metadata

Authors
van Spronsen, M., & Hoogenraad, C. C.
Affiliations
Erasmus MC (NL)
Corresponding author
Hoogenraad, Casper C.
ORCID
Hoogenraad, Casper C.
Venue
Current Neurology and Neuroscience Reports
Publisher
Springer Science and Business Media LLC
Published
2010-03-18
Volume
10
Issue
3
Pages
207-214
ISSN
  • 1528-4042 (ISSN-L)
  • 1534-6293
DOI
10.1007/s11910-010-0104-8
PMC
PMC2857788
OpenAlex
W2098229885
Cited by
345
References
50
Citations by year
2026: 5 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 22 · 2021: 18 · 2020: 21 · 2019: 20 · 2018: 29 · 2017: 21 · 2016: 25 · 2015: 26 · 2014: 22 · 2013: 24 · 2012: 38
FWCI
2.66
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Current Neurology and Neuroscience Reports (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
Funders
  • ZonMw
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords
dendritic spines, dendritic spine morphology, excitatory synapses, inhibitory synapses, synaptic transmission, postsynaptic density, glutamate receptors, mental illness, neurological disorders, autism spectrum disorder, intellectual disability, Alzheimer's disease, addiction, synapse number
MeSH terms
Mental Disorders, Humans, Models, Biological, Nervous System Diseases, Neuronal Plasticity, Neurons, Synapses, Dendritic Spines

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