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  1. Live a1a77a6096e3
    4/26/2026, 2:20:41 PM
    Content snapshot 
    {
  "content_md": "# Huntington's Disease: Corticostriatal Synaptic Vulnerability\n\n## Overview\n\nCorticostriatal synaptic vulnerability is a hallmark feature of Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the [HTT](/genes/htt) gene encoding huntingtin protein. The corticostriatal pathway, which connects cortical neurons to the striatum, undergoes progressive degeneration that underlies many of the characteristic motor and cognitive symptoms of HD.\n\n## The Corticostriatal Pathway in Huntington's Disease\n\n### Anatomical Background\n\nThe corticostriatal pathway is one of the major excitatory input systems to the basal ganglia. Cortical layer 5 pyramidal neurons send dense glutamatergic projections to the striatum, where they synapse onto medium spiny neurons (MSNs), the principal output neurons of the striatum. This pathway is critical for motor initiation, habit formation, and procedural learning.\n\nIn Huntington's disease, both the cortical neurons that send projections and the striatal neurons that receive them undergo degeneration, leading to a \"dying-back\" pattern of neurodegeneration that begins at the synaptic terminals and progresses proximally toward the cell bodies.\n\n## Molecular Mechanisms of Synaptic Vulnerability\n\n### Mutant Huntingtin-Induced Synaptic Dysfunction\n\nThe mutant huntingtin protein (mHTT) exerts toxic effects on synapses through multiple mechanisms:\n\n#### 1. Loss of Normal Huntingtin Function\n\nWild-type huntingtin (wtHTT) is essential for:\n- Synaptic vesicle trafficking and neurotransmitter release\n- Dendritic spine maintenance and plasticity\n- Transcriptional regulation of synaptic proteins\n- Autophagy and clearance of synaptic debris\n\nThe mutation leads to loss of these protective functions, making synapses more vulnerable to stress and damage.\n\n#### 2. Toxic Gain-of-Function\n\nMutant huntingtin forms:\n- Aberrant protein aggregates that sequester essential synaptic proteins\n- Transcriptional dysregulation of synaptic genes\n- Disrupted mitochondrial function at synapses\n- Impaired proteostasis mechanisms\n\n#### 3. Excitotoxicity\n\nExcitotoxicity is a major contributor to corticostriatal vulnerability in HD:\n\n**Glutamate Receptor Dysfunction:**\n- NMDA receptor (NMDAR) hyperactivity contributes to calcium dysregulation\n- Altered AMPA receptor (AMPAR) trafficking reduces synaptic stability\n- Metabotropic glutamate receptors (mGluRs) show abnormal signaling\n\n**Calcium Homeostasis Disruption:**\n- Endoplasmic reticulum stress at synapses\n- Mitochondrial calcium overload\n- Activation of calcium-dependent degradative enzymes\n\n### Synaptic Protein Alterations in HD\n\n| Protein Category | Changes in HD | Functional Impact |\n|------------------|---------------|------------------|\n| Presynaptic proteins | Reduced synaptophysin, synaptobrevin | Impaired vesicle release |\n| Postsynaptic density | Altered PSD-95, Homer | Disrupted signaling scaffolds |\n| Ion channels | Cav1.2, Kv4.2 dysregulation | Abnormal excitability |\n| Neurotrophin receptors | TrkB signaling impairment | Reduced synaptic plasticity |\n\n## Cellular and Circuit-Level Changes\n\n### Medium Spiny Neuron Vulnerability\n\nMedium spiny neurons (MSNs), the primary target of corticostriatal inputs, show particular vulnerability in HD:\n\n#### Dendritic Spine Loss\n- Early loss of dendritic spines on MSNs precedes behavioral deficits\n- Spine loss is most pronounced on the distal dendrites where corticostriatal inputs terminate\n- This reflects the vulnerability of excitatory synapses specifically\n\n#### Synaptic Input Remodeling\n- Loss of corticostriatal excitatory inputs\n- Increased inhibitory inputs from local interneurons\n- Imbalance between excitation and inhibition\n\n#### Electrophysiological Changes\n- Resting membrane potential depolarization\n- Reduced input resistance\n- Abnormal firing patterns\n- Impaired long-term potentiation (LTP) and depression (LTD)\n\n### Cortical Neuron Degeneration\n\nThe cortical neurons that provide input to the striatum also degenerate:\n- Layer 5 pyramidal neurons show reduced corticostriatal axon integrity\n- Cortical hyperexcitability precedes striatal degeneration\n- Decreased brain-derived neurotrophic factor (BDNF) transport from cortex to striatum\n\n## Stages of Corticostriatal Degeneration\n\n### Preclinical/Presymptomatic Stage\n- Subtle synaptic plasticity deficits\n- Early dendritic spine changes\n- Normal motor behavior\n\n### Early HD\n- Significant spine loss on MSNs\n- Corticostriatal connectivity reduction\n- Minor motor and cognitive changes\n\n### Moderate HD\n- Marked corticostriatal synaptic loss\n- Severe behavioral symptoms\n- Neuronal atrophy begins\n\n### Advanced HD\n- Extensive degeneration of corticostriatal pathway\n- Severe motor and cognitive impairment\n- Widespread brain atrophy\n\n## Therapeutic Implications\n\n### Targeting Corticostriatal Synapses\n\n#### 1. Synaptic Protection\n- NMDA receptor modulators to reduce excitotoxicity\n- Calcium channel blockers to protect synaptic calcium homeostasis\n- Synaptic protein stabilizers\n\n#### 2. Restoring Synaptic Function\n- BDNF mimetics to support synaptic plasticity\n- AMPA receptor positive allosteric modulators\n- Synaptic vesicle cycle enhancers\n\n#### 3. Disease-Modifying Approaches\n- Huntingtin-lowering therapies (ASOs, CRISPR)\n- Autophagy enhancers to clear toxic protein aggregates\n- Transcriptional regulators to restore synaptic gene expression\n\n### Clinical Trial Implications\n\nCorticostriatal synaptic integrity is increasingly used as a biomarker:\n- PET imaging of synaptic vesicle protein 2A (SV2A)\n- Cerebrospinal fluid synaptic biomarkers (neurogranin, SNAP-25)\n- Structural MRI measures of striatal volume\n\n## Pathway Diagram: Corticostriatal Synaptic Vulnerability\n\n```mermaid\nflowchart TD\n    A[\"mHTT Expression\"] --> B[\"Cortical Neurons\"]\n    A --> C[\"Striatal Medium Spiny Neurons\"]\n\n    B --> D[\"Synaptic Dysfunction\"]\n    C --> D\n\n    D --> E[\"Glutamate Excitotoxicity\"]\n    D --> F[\"NMDA Receptor Dysregulation\"]\n    D --> G[\"Cav1.2 Channel Dysfunction\"]\n\n    E --> H[\"Calcium Dysregulation\"]\n    F --> H\n    G --> H\n\n    H --> I[\"Mitochondrial Permeability Transition\"]\n    I --> J[\"ATP Depletion\"]\n\n    J --> K[\"Striatal Neuron Death\"]\n    K --> L[\"Huntington's Disease Phenotype\"]\n\n    style A fill:#1a0a1f,stroke:#333\n    style L fill:#3e2200,stroke:#333\n```\n\n## See Also\n\n- [Huntington's Disease](/diseases/huntingtons)\n- [Huntingtin Protein](/proteins/huntingtin-protein)\n- [Medium Spiny Neurons](/cell-types/medium-spiny-neurons)\n- [Excitotoxicity in Neurodegeneration](/mechanisms/excitotoxicity)\n- [Huntington's CAG Repeat Expansion](/mechanisms/huntingtons-cag-repeat-expansion)\n- [BDNF Signaling in Neurodegeneration](/mechanisms/bdnf-signaling-neurodegeneration)\n\n## External Links\n\n- [Huntington's Disease Society of America](https://hdsa.org/)\n- [CHDI Foundation](https://chdifoundation.org/)\n- [NIH - Huntington's Disease Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page)\n- [ClinicalTrials.gov - Huntington's Disease](https://clinicaltrials.gov/search?cond=Huntington+Disease)\n\n## References\n\n1. [Reiner & Deng, Huntington's disease: The corticostriatal circuit (2021)](https://doi.org/10.3233/JHD-200435)\n2. [Parent & Hazrati, Functional anatomy of the basal ganglia (1995)](https://doi.org/10.1016/0165-0173(94)00007-C)\n3. [Saudou & Humbert, The biology of huntingtin (2016)](https://doi.org/10.1016/j.neuron.2016.02.003)\n4. [Plotkin & Surmeier, Corticostriatal synaptic adaptations in HD (2015)](https://doi.org/10.1016/j.conb.2015.01.020)\n5. [Raymond et al., Pathophysiology of Huntington's disease (2014)](https://doi.org/10.1098/rstb.2013.0477)\n6. [Spires et al., Environmental enrichment in HD mouse models (2004)](https://doi.org/10.1523/JNEUROSCI.1658-03.2004)\n7. [Milnerwood & Raymond, Corticostriatal synaptic function in HD (2010)](https://doi.org/10.1016/j.pnpbp.2009.12.003)\n8. [Andre et al., Dopamine and glutamate in Huntington's disease (2010)](https://doi.org/10.1517/14728222.2010.487874)\n9. [Ferrante, Mouse models of Huntington's disease (2009)](https://doi.org/10.1016/j.bbadis.2009.04.001)\n10. [Ross & Tabrizi, Huntington's disease: From molecular pathogenesis to clinical treatment (2011)](https://doi.org/10.1016/S1474-4422(10)70245-3)",
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  "refs_json": {
    "ross2011": {
      "doi": "10.1016/S1474-4422(10)70245-3",
      "year": 2011,
      "title": "Huntington's disease: From molecular pathogenesis to clinical treatment",
      "authors": "Ross CA, Tabrizi SJ"
    },
    "andre2010": {
      "doi": "10.1517/14728222.2010.487874",
      "year": 2010,
      "title": "Dopamine and glutamate in Huntington's disease: A balanced aim?",
      "authors": "Andre VM, Cepeda C, Levine MS"
    },
    "parent1995": {
      "doi": "10.1016/0165-0173(94)00007-C",
      "year": 1995,
      "title": "Functional anatomy of the basal ganglia",
      "authors": "Parent A, Hazrati LN"
    },
    "reiner2021": {
      "doi": "10.3233/JHD-200435",
      "year": 2021,
      "title": "Huntington's disease: The current state of research on the corticostriatal circuit",
      "authors": "Reiner A, Deng YP"
    },
    "saudou2016": {
      "doi": "10.1016/j.neuron.2016.02.003",
      "year": 2016,
      "title": "The biology of huntingtin",
      "authors": "Saudou F, Humbert S"
    },
    "spires2004": {
      "doi": "10.1523/JNEUROSCI.1658-03.2004",
      "year": 2004,
      "title": "Environmental enrichment rescues protein deficits in a mouse model of Huntington's disease",
      "authors": "Spires TL, Grote HE, Varshney NK, et al"
    },
    "plotkin2015": {
      "doi": "10.1016/j.conb.2015.01.020",
      "year": 2015,
      "title": "Corticostriatal synaptic adaptations in Huntington's disease",
      "authors": "Plotkin JL, Surmeier DJ"
    },
    "raymond2014": {
      "doi": "10.1098/rstb.2013.0477",
      "year": 2014,
      "title": "Pathophysiology of Huntington's disease: Time-dependent alterations in synaptic activity and neuronal excitability",
      "authors": "Raymond LA, Andre VM, Cepeda C, et al"
    },
    "ferrante2009": {
      "doi": "10.1016/j.bbadis.2009.04.001",
      "year": 2009,
      "title": "Mouse models of Huntington's disease and methodological considerations for therapeutic trials",
      "authors": "Ferrante RJ"
    },
    "milnerwood2010": {
      "doi": "10.1016/j.pnpbp.2009.12.003",
      "year": 2010,
      "title": "Corticostriatal synaptic function in mouse models of Huntington's disease: Early changes and late rescue",
      "authors": "Milnerwood AJ, Raymond LA"
    }
  },
  "epistemic_status": "provisional",
  "word_count": 942,
  "source_repo": "NeuroWiki"
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  2. v4
    Content snapshot 
    {
  "content_md": "# Huntington's Disease: Corticostriatal Synaptic Vulnerability\n\n## Overview\n\nCorticostriatal synaptic vulnerability is a hallmark feature of Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the [HTT](/genes/htt) gene encoding huntingtin protein. The corticostriatal pathway, which connects cortical neurons to the striatum, undergoes progressive degeneration that underlies many of the characteristic motor and cognitive symptoms of HD.\n\n## The Corticostriatal Pathway in Huntington's Disease\n\n### Anatomical Background\n\nThe corticostriatal pathway is one of the major excitatory input systems to the basal ganglia. Cortical layer 5 pyramidal neurons send dense glutamatergic projections to the striatum, where they synapse onto medium spiny neurons (MSNs), the principal output neurons of the striatum. This pathway is critical for motor initiation, habit formation, and procedural learning.\n\nIn Huntington's disease, both the cortical neurons that send projections and the striatal neurons that receive them undergo degeneration, leading to a \"dying-back\" pattern of neurodegeneration that begins at the synaptic terminals and progresses proximally toward the cell bodies.\n\n## Molecular Mechanisms of Synaptic Vulnerability\n\n### Mutant Huntingtin-Induced Synaptic Dysfunction\n\nThe mutant huntingtin protein (mHTT) exerts toxic effects on synapses through multiple mechanisms:\n\n#### 1. Loss of Normal Huntingtin Function\n\nWild-type huntingtin (wtHTT) is essential for:\n- Synaptic vesicle trafficking and neurotransmitter release\n- Dendritic spine maintenance and plasticity\n- Transcriptional regulation of synaptic proteins\n- Autophagy and clearance of synaptic debris\n\nThe mutation leads to loss of these protective functions, making synapses more vulnerable to stress and damage.\n\n#### 2. Toxic Gain-of-Function\n\nMutant huntingtin forms:\n- Aberrant protein aggregates that sequester essential synaptic proteins\n- Transcriptional dysregulation of synaptic genes\n- Disrupted mitochondrial function at synapses\n- Impaired proteostasis mechanisms\n\n#### 3. Excitotoxicity\n\nExcitotoxicity is a major contributor to corticostriatal vulnerability in HD:\n\n**Glutamate Receptor Dysfunction:**\n- NMDA receptor (NMDAR) hyperactivity contributes to calcium dysregulation\n- Altered AMPA receptor (AMPAR) trafficking reduces synaptic stability\n- Metabotropic glutamate receptors (mGluRs) show abnormal signaling\n\n**Calcium Homeostasis Disruption:**\n- Endoplasmic reticulum stress at synapses\n- Mitochondrial calcium overload\n- Activation of calcium-dependent degradative enzymes\n\n### Synaptic Protein Alterations in HD\n\n| Protein Category | Changes in HD | Functional Impact |\n|------------------|---------------|------------------|\n| Presynaptic proteins | Reduced synaptophysin, synaptobrevin | Impaired vesicle release |\n| Postsynaptic density | Altered PSD-95, Homer | Disrupted signaling scaffolds |\n| Ion channels | Cav1.2, Kv4.2 dysregulation | Abnormal excitability |\n| Neurotrophin receptors | TrkB signaling impairment | Reduced synaptic plasticity |\n\n## Cellular and Circuit-Level Changes\n\n### Medium Spiny Neuron Vulnerability\n\nMedium spiny neurons (MSNs), the primary target of corticostriatal inputs, show particular vulnerability in HD:\n\n#### Dendritic Spine Loss\n- Early loss of dendritic spines on MSNs precedes behavioral deficits\n- Spine loss is most pronounced on the distal dendrites where corticostriatal inputs terminate\n- This reflects the vulnerability of excitatory synapses specifically\n\n#### Synaptic Input Remodeling\n- Loss of corticostriatal excitatory inputs\n- Increased inhibitory inputs from local interneurons\n- Imbalance between excitation and inhibition\n\n#### Electrophysiological Changes\n- Resting membrane potential depolarization\n- Reduced input resistance\n- Abnormal firing patterns\n- Impaired long-term potentiation (LTP) and depression (LTD)\n\n### Cortical Neuron Degeneration\n\nThe cortical neurons that provide input to the striatum also degenerate:\n- Layer 5 pyramidal neurons show reduced corticostriatal axon integrity\n- Cortical hyperexcitability precedes striatal degeneration\n- Decreased brain-derived neurotrophic factor (BDNF) transport from cortex to striatum\n\n## Stages of Corticostriatal Degeneration\n\n### Preclinical/Presymptomatic Stage\n- Subtle synaptic plasticity deficits\n- Early dendritic spine changes\n- Normal motor behavior\n\n### Early HD\n- Significant spine loss on MSNs\n- Corticostriatal connectivity reduction\n- Minor motor and cognitive changes\n\n### Moderate HD\n- Marked corticostriatal synaptic loss\n- Severe behavioral symptoms\n- Neuronal atrophy begins\n\n### Advanced HD\n- Extensive degeneration of corticostriatal pathway\n- Severe motor and cognitive impairment\n- Widespread brain atrophy\n\n## Therapeutic Implications\n\n### Targeting Corticostriatal Synapses\n\n#### 1. Synaptic Protection\n- NMDA receptor modulators to reduce excitotoxicity\n- Calcium channel blockers to protect synaptic calcium homeostasis\n- Synaptic protein stabilizers\n\n#### 2. Restoring Synaptic Function\n- BDNF mimetics to support synaptic plasticity\n- AMPA receptor positive allosteric modulators\n- Synaptic vesicle cycle enhancers\n\n#### 3. Disease-Modifying Approaches\n- Huntingtin-lowering therapies (ASOs, CRISPR)\n- Autophagy enhancers to clear toxic protein aggregates\n- Transcriptional regulators to restore synaptic gene expression\n\n### Clinical Trial Implications\n\nCorticostriatal synaptic integrity is increasingly used as a biomarker:\n- PET imaging of synaptic vesicle protein 2A (SV2A)\n- Cerebrospinal fluid synaptic biomarkers (neurogranin, SNAP-25)\n- Structural MRI measures of striatal volume\n\n## Pathway Diagram: Corticostriatal Synaptic Vulnerability\n\nflowchart TD\n    A[\"mHTT Expression\"] --> B[\"Cortical Neurons\"]\n    A --> C[\"Striatal Medium Spiny Neurons\"]\n\n    B --> D[\"Synaptic Dysfunction\"]\n    C --> D\n\n    D --> E[\"Glutamate Excitotoxicity\"]\n    D --> F[\"NMDA Receptor Dysregulation\"]\n    D --> G[\"Cav1.2 Channel Dysfunction\"]\n\n    E --> H[\"Calcium Dysregulation\"]\n    F --> H\n    G --> H\n\n    H --> I[\"Mitochondrial Permeability Transition\"]\n    I --> J[\"ATP Depletion\"]\n\n    J --> K[\"Striatal Neuron Death\"]\n    K --> L[\"Huntington's Disease Phenotype\"]\n\n    style A fill:#1a0a1f,stroke:#333\n    style L fill:#3e2200,stroke:#333\n\n## See Also\n\n- [Huntington's Disease](/diseases/huntingtons)\n- [Huntingtin Protein](/proteins/huntingtin-protein)\n- [Medium Spiny Neurons](/cell-types/medium-spiny-neurons)\n- [Excitotoxicity in Neurodegeneration](/mechanisms/excitotoxicity)\n- [Huntington's CAG Repeat Expansion](/mechanisms/huntingtons-cag-repeat-expansion)\n- [BDNF Signaling in Neurodegeneration](/mechanisms/bdnf-signaling-neurodegeneration)\n\n## External Links\n\n- [Huntington's Disease Society of America](https://hdsa.org/)\n- [CHDI Foundation](https://chdifoundation.org/)\n- [NIH - Huntington's Disease Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page)\n- [ClinicalTrials.gov - Huntington's Disease](https://clinicaltrials.gov/search?cond=Huntington+Disease)\n\n## References\n\n1. [Reiner & Deng, Huntington's disease: The corticostriatal circuit (2021)](https://doi.org/10.3233/JHD-200435)\n2. [Parent & Hazrati, Functional anatomy of the basal ganglia (1995)](https://doi.org/10.1016/0165-0173(94)00007-C)\n3. [Saudou & Humbert, The biology of huntingtin (2016)](https://doi.org/10.1016/j.neuron.2016.02.003)\n4. [Plotkin & Surmeier, Corticostriatal synaptic adaptations in HD (2015)](https://doi.org/10.1016/j.conb.2015.01.020)\n5. [Raymond et al., Pathophysiology of Huntington's disease (2014)](https://doi.org/10.1098/rstb.2013.0477)\n6. [Spires et al., Environmental enrichment in HD mouse models (2004)](https://doi.org/10.1523/JNEUROSCI.1658-03.2004)\n7. [Milnerwood & Raymond, Corticostriatal synaptic function in HD (2010)](https://doi.org/10.1016/j.pnpbp.2009.12.003)\n8. [Andre et al., Dopamine and glutamate in Huntington's disease (2010)](https://doi.org/10.1517/14728222.2010.487874)\n9. [Ferrante, Mouse models of Huntington's disease (2009)](https://doi.org/10.1016/j.bbadis.2009.04.001)\n10. [Ross & Tabrizi, Huntington's disease: From molecular pathogenesis to clinical treatment (2011)](https://doi.org/10.1016/S1474-4422(10)70245-3)",
  "entity_type": "mechanism"
}
  3. v3
    Content snapshot 
    {
  "content_md": "# Huntington's Disease: Corticostriatal Synaptic Vulnerability\n\n## Overview\n\nCorticostriatal synaptic vulnerability is a hallmark feature of Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the [HTT](/genes/htt) gene encoding huntingtin protein. The corticostriatal pathway, which connects cortical neurons to the striatum, undergoes progressive degeneration that underlies many of the characteristic motor and cognitive symptoms of HD.\n\n## The Corticostriatal Pathway in Huntington's Disease\n\n### Anatomical Background\n\nThe corticostriatal pathway is one of the major excitatory input systems to the basal ganglia. Cortical layer 5 pyramidal neurons send dense glutamatergic projections to the striatum, where they synapse onto medium spiny neurons (MSNs), the principal output neurons of the striatum. This pathway is critical for motor initiation, habit formation, and procedural learning.\n\nIn Huntington's disease, both the cortical neurons that send projections and the striatal neurons that receive them undergo degeneration, leading to a \"dying-back\" pattern of neurodegeneration that begins at the synaptic terminals and progresses proximally toward the cell bodies.\n\n## Molecular Mechanisms of Synaptic Vulnerability\n\n### Mutant Huntingtin-Induced Synaptic Dysfunction\n\nThe mutant huntingtin protein (mHTT) exerts toxic effects on synapses through multiple mechanisms:\n\n#### 1. Loss of Normal Huntingtin Function\n\nWild-type huntingtin (wtHTT) is essential for:\n- Synaptic vesicle trafficking and neurotransmitter release\n- Dendritic spine maintenance and plasticity\n- Transcriptional regulation of synaptic proteins\n- Autophagy and clearance of synaptic debris\n\nThe mutation leads to loss of these protective functions, making synapses more vulnerable to stress and damage.\n\n#### 2. Toxic Gain-of-Function\n\nMutant huntingtin forms:\n- Aberrant protein aggregates that sequester essential synaptic proteins\n- Transcriptional dysregulation of synaptic genes\n- Disrupted mitochondrial function at synapses\n- Impaired proteostasis mechanisms\n\n#### 3. Excitotoxicity\n\nExcitotoxicity is a major contributor to corticostriatal vulnerability in HD:\n\n**Glutamate Receptor Dysfunction:**\n- NMDA receptor (NMDAR) hyperactivity contributes to calcium dysregulation\n- Altered AMPA receptor (AMPAR) trafficking reduces synaptic stability\n- Metabotropic glutamate receptors (mGluRs) show abnormal signaling\n\n**Calcium Homeostasis Disruption:**\n- Endoplasmic reticulum stress at synapses\n- Mitochondrial calcium overload\n- Activation of calcium-dependent degradative enzymes\n\n### Synaptic Protein Alterations in HD\n\n| Protein Category | Changes in HD | Functional Impact |\n|------------------|---------------|------------------|\n| Presynaptic proteins | Reduced synaptophysin, synaptobrevin | Impaired vesicle release |\n| Postsynaptic density | Altered PSD-95, Homer | Disrupted signaling scaffolds |\n| Ion channels | Cav1.2, Kv4.2 dysregulation | Abnormal excitability |\n| Neurotrophin receptors | TrkB signaling impairment | Reduced synaptic plasticity |\n\n## Cellular and Circuit-Level Changes\n\n### Medium Spiny Neuron Vulnerability\n\nMedium spiny neurons (MSNs), the primary target of corticostriatal inputs, show particular vulnerability in HD:\n\n#### Dendritic Spine Loss\n- Early loss of dendritic spines on MSNs precedes behavioral deficits\n- Spine loss is most pronounced on the distal dendrites where corticostriatal inputs terminate\n- This reflects the vulnerability of excitatory synapses specifically\n\n#### Synaptic Input Remodeling\n- Loss of corticostriatal excitatory inputs\n- Increased inhibitory inputs from local interneurons\n- Imbalance between excitation and inhibition\n\n#### Electrophysiological Changes\n- Resting membrane potential depolarization\n- Reduced input resistance\n- Abnormal firing patterns\n- Impaired long-term potentiation (LTP) and depression (LTD)\n\n### Cortical Neuron Degeneration\n\nThe cortical neurons that provide input to the striatum also degenerate:\n- Layer 5 pyramidal neurons show reduced corticostriatal axon integrity\n- Cortical hyperexcitability precedes striatal degeneration\n- Decreased brain-derived neurotrophic factor (BDNF) transport from cortex to striatum\n\n## Stages of Corticostriatal Degeneration\n\n### Preclinical/Presymptomatic Stage\n- Subtle synaptic plasticity deficits\n- Early dendritic spine changes\n- Normal motor behavior\n\n### Early HD\n- Significant spine loss on MSNs\n- Corticostriatal connectivity reduction\n- Minor motor and cognitive changes\n\n### Moderate HD\n- Marked corticostriatal synaptic loss\n- Severe behavioral symptoms\n- Neuronal atrophy begins\n\n### Advanced HD\n- Extensive degeneration of corticostriatal pathway\n- Severe motor and cognitive impairment\n- Widespread brain atrophy\n\n## Therapeutic Implications\n\n### Targeting Corticostriatal Synapses\n\n#### 1. Synaptic Protection\n- NMDA receptor modulators to reduce excitotoxicity\n- Calcium channel blockers to protect synaptic calcium homeostasis\n- Synaptic protein stabilizers\n\n#### 2. Restoring Synaptic Function\n- BDNF mimetics to support synaptic plasticity\n- AMPA receptor positive allosteric modulators\n- Synaptic vesicle cycle enhancers\n\n#### 3. Disease-Modifying Approaches\n- Huntingtin-lowering therapies (ASOs, CRISPR)\n- Autophagy enhancers to clear toxic protein aggregates\n- Transcriptional regulators to restore synaptic gene expression\n\n### Clinical Trial Implications\n\nCorticostriatal synaptic integrity is increasingly used as a biomarker:\n- PET imaging of synaptic vesicle protein 2A (SV2A)\n- Cerebrospinal fluid synaptic biomarkers (neurogranin, SNAP-25)\n- Structural MRI measures of striatal volume\n\n## Pathway Diagram: Corticostriatal Synaptic Vulnerability\n\n```mermaid\nflowchart TD\n    A[\"mHTT Expression\"] --> B[\"Cortical Neurons\"]\n    A --> C[\"Striatal Medium Spiny Neurons\"]\n\n    B --> D[\"Synaptic Dysfunction\"]\n    C --> D\n\n    D --> E[\"Glutamate Excitotoxicity\"]\n    D --> F[\"NMDA Receptor Dysregulation\"]\n    D --> G[\"Cav1.2 Channel Dysfunction\"]\n\n    E --> H[\"Calcium Dysregulation\"]\n    F --> H\n    G --> H\n\n    H --> I[\"Mitochondrial Permeability Transition\"]\n    I --> J[\"ATP Depletion\"]\n\n    J --> K[\"Striatal Neuron Death\"]\n    K --> L[\"Huntington's Disease Phenotype\"]\n\n    style A fill:#1a0a1f,stroke:#333\n    style L fill:#3e2200,stroke:#333\n```\n\n## See Also\n\n- [Huntington's Disease](/diseases/huntingtons)\n- [Huntingtin Protein](/proteins/huntingtin-protein)\n- [Medium Spiny Neurons](/cell-types/medium-spiny-neurons)\n- [Excitotoxicity in Neurodegeneration](/mechanisms/excitotoxicity)\n- [Huntington's CAG Repeat Expansion](/mechanisms/huntingtons-cag-repeat-expansion)\n- [BDNF Signaling in Neurodegeneration](/mechanisms/bdnf-signaling-neurodegeneration)\n\n## External Links\n\n- [Huntington's Disease Society of America](https://hdsa.org/)\n- [CHDI Foundation](https://chdifoundation.org/)\n- [NIH - Huntington's Disease Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page)\n- [ClinicalTrials.gov - Huntington's Disease](https://clinicaltrials.gov/search?cond=Huntington+Disease)\n\n## References\n\n1. [Reiner & Deng, Huntington's disease: The corticostriatal circuit (2021)](https://doi.org/10.3233/JHD-200435)\n2. [Parent & Hazrati, Functional anatomy of the basal ganglia (1995)](https://doi.org/10.1016/0165-0173(94)00007-C)\n3. [Saudou & Humbert, The biology of huntingtin (2016)](https://doi.org/10.1016/j.neuron.2016.02.003)\n4. [Plotkin & Surmeier, Corticostriatal synaptic adaptations in HD (2015)](https://doi.org/10.1016/j.conb.2015.01.020)\n5. [Raymond et al., Pathophysiology of Huntington's disease (2014)](https://doi.org/10.1098/rstb.2013.0477)\n6. [Spires et al., Environmental enrichment in HD mouse models (2004)](https://doi.org/10.1523/JNEUROSCI.1658-03.2004)\n7. [Milnerwood & Raymond, Corticostriatal synaptic function in HD (2010)](https://doi.org/10.1016/j.pnpbp.2009.12.003)\n8. [Andre et al., Dopamine and glutamate in Huntington's disease (2010)](https://doi.org/10.1517/14728222.2010.487874)\n9. [Ferrante, Mouse models of Huntington's disease (2009)](https://doi.org/10.1016/j.bbadis.2009.04.001)\n10. [Ross & Tabrizi, Huntington's disease: From molecular pathogenesis to clinical treatment (2011)](https://doi.org/10.1016/S1474-4422(10)70245-3)",
  "entity_type": "mechanism"
}
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    {
  "content_md": "# Huntington's Disease: Corticostriatal Synaptic Vulnerability\n\n## Overview\n\nCorticostriatal synaptic vulnerability is a hallmark feature of Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the [HTT](/genes/htt) gene encoding huntingtin protein. The corticostriatal pathway, which connects cortical neurons to the striatum, undergoes progressive degeneration that underlies many of the characteristic motor and cognitive symptoms of HD.\n\n## The Corticostriatal Pathway in Huntington's Disease\n\n### Anatomical Background\n\nThe corticostriatal pathway is one of the major excitatory input systems to the basal ganglia. Cortical layer 5 pyramidal neurons send dense glutamatergic projections to the striatum, where they synapse onto medium spiny neurons (MSNs), the principal output neurons of the striatum. This pathway is critical for motor initiation, habit formation, and procedural learning.\n\nIn Huntington's disease, both the cortical neurons that send projections and the striatal neurons that receive them undergo degeneration, leading to a \"dying-back\" pattern of neurodegeneration that begins at the synaptic terminals and progresses proximally toward the cell bodies.\n\n## Molecular Mechanisms of Synaptic Vulnerability\n\n### Mutant Huntingtin-Induced Synaptic Dysfunction\n\nThe mutant huntingtin protein (mHTT) exerts toxic effects on synapses through multiple mechanisms:\n\n#### 1. Loss of Normal Huntingtin Function\n\nWild-type huntingtin (wtHTT) is essential for:\n- Synaptic vesicle trafficking and neurotransmitter release\n- Dendritic spine maintenance and plasticity\n- Transcriptional regulation of synaptic proteins\n- Autophagy and clearance of synaptic debris\n\nThe mutation leads to loss of these protective functions, making synapses more vulnerable to stress and damage.\n\n#### 2. Toxic Gain-of-Function\n\nMutant huntingtin forms:\n- Aberrant protein aggregates that sequester essential synaptic proteins\n- Transcriptional dysregulation of synaptic genes\n- Disrupted mitochondrial function at synapses\n- Impaired proteostasis mechanisms\n\n#### 3. Excitotoxicity\n\nExcitotoxicity is a major contributor to corticostriatal vulnerability in HD:\n\n**Glutamate Receptor Dysfunction:**\n- NMDA receptor (NMDAR) hyperactivity contributes to calcium dysregulation\n- Altered AMPA receptor (AMPAR) trafficking reduces synaptic stability\n- Metabotropic glutamate receptors (mGluRs) show abnormal signaling\n\n**Calcium Homeostasis Disruption:**\n- Endoplasmic reticulum stress at synapses\n- Mitochondrial calcium overload\n- Activation of calcium-dependent degradative enzymes\n\n### Synaptic Protein Alterations in HD\n\n| Protein Category | Changes in HD | Functional Impact |\n|------------------|---------------|------------------|\n| Presynaptic proteins | Reduced synaptophysin, synaptobrevin | Impaired vesicle release |\n| Postsynaptic density | Altered PSD-95, Homer | Disrupted signaling scaffolds |\n| Ion channels | Cav1.2, Kv4.2 dysregulation | Abnormal excitability |\n| Neurotrophin receptors | TrkB signaling impairment | Reduced synaptic plasticity |\n\n## Cellular and Circuit-Level Changes\n\n### Medium Spiny Neuron Vulnerability\n\nMedium spiny neurons (MSNs), the primary target of corticostriatal inputs, show particular vulnerability in HD:\n\n#### Dendritic Spine Loss\n- Early loss of dendritic spines on MSNs precedes behavioral deficits\n- Spine loss is most pronounced on the distal dendrites where corticostriatal inputs terminate\n- This reflects the vulnerability of excitatory synapses specifically\n\n#### Synaptic Input Remodeling\n- Loss of corticostriatal excitatory inputs\n- Increased inhibitory inputs from local interneurons\n- Imbalance between excitation and inhibition\n\n#### Electrophysiological Changes\n- Resting membrane potential depolarization\n- Reduced input resistance\n- Abnormal firing patterns\n- Impaired long-term potentiation (LTP) and depression (LTD)\n\n### Cortical Neuron Degeneration\n\nThe cortical neurons that provide input to the striatum also degenerate:\n- Layer 5 pyramidal neurons show reduced corticostriatal axon integrity\n- Cortical hyperexcitability precedes striatal degeneration\n- Decreased brain-derived neurotrophic factor (BDNF) transport from cortex to striatum\n\n## Stages of Corticostriatal Degeneration\n\n### Preclinical/Presymptomatic Stage\n- Subtle synaptic plasticity deficits\n- Early dendritic spine changes\n- Normal motor behavior\n\n### Early HD\n- Significant spine loss on MSNs\n- Corticostriatal connectivity reduction\n- Minor motor and cognitive changes\n\n### Moderate HD\n- Marked corticostriatal synaptic loss\n- Severe behavioral symptoms\n- Neuronal atrophy begins\n\n### Advanced HD\n- Extensive degeneration of corticostriatal pathway\n- Severe motor and cognitive impairment\n- Widespread brain atrophy\n\n## Therapeutic Implications\n\n### Targeting Corticostriatal Synapses\n\n#### 1. Synaptic Protection\n- NMDA receptor modulators to reduce excitotoxicity\n- Calcium channel blockers to protect synaptic calcium homeostasis\n- Synaptic protein stabilizers\n\n#### 2. Restoring Synaptic Function\n- BDNF mimetics to support synaptic plasticity\n- AMPA receptor positive allosteric modulators\n- Synaptic vesicle cycle enhancers\n\n#### 3. Disease-Modifying Approaches\n- Huntingtin-lowering therapies (ASOs, CRISPR)\n- Autophagy enhancers to clear toxic protein aggregates\n- Transcriptional regulators to restore synaptic gene expression\n\n### Clinical Trial Implications\n\nCorticostriatal synaptic integrity is increasingly used as a biomarker:\n- PET imaging of synaptic vesicle protein 2A (SV2A)\n- Cerebrospinal fluid synaptic biomarkers (neurogranin, SNAP-25)\n- Structural MRI measures of striatal volume\n\n## Pathway Diagram: Corticostriatal Synaptic Vulnerability\n\n```mermaid\nflowchart TD\n    A[\"mHTT Expression\"] --> B[\"Cortical Neurons\"]\n    A --> C[\"Striatal Medium Spiny Neurons\"]\n\n    B --> D[\"Synaptic Dysfunction\"]\n    C --> D\n\n    D --> E[\"Glutamate Excitotoxicity\"]\n    D --> F[\"NMDA Receptor Dysregulation\"]\n    D --> G[\"Cav1.2 Channel Dysfunction\"]\n\n    E --> H[\"Calcium Dysregulation\"]\n    F --> H\n    G --> H\n\n    H --> I[\"Mitochondrial Permeability Transition\"]\n    I --> J[\"ATP Depletion\"]\n\n    J --> K[\"Striatal Neuron Death\"]\n    K --> L[\"Huntington's Disease Phenotype\"]\n\n    style A fill:#1a0a1f,stroke:#333\n    style L fill:#3e2200,stroke:#333\n```\n\n## See Also\n\n- [Huntington's Disease](/diseases/huntingtons)\n- [Huntingtin Protein](/proteins/huntingtin-protein)\n- [Medium Spiny Neurons](/cell-types/medium-spiny-neurons)\n- [Excitotoxicity in Neurodegeneration](/mechanisms/excitotoxicity)\n- [Huntington's CAG Repeat Expansion](/mechanisms/huntingtons-cag-repeat-expansion)\n- [BDNF Signaling in Neurodegeneration](/mechanisms/bdnf-signaling-neurodegeneration)\n\n## External Links\n\n- [Huntington's Disease Society of America](https://hdsa.org/)\n- [CHDI Foundation](https://chdifoundation.org/)\n- [NIH - Huntington's Disease Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page)\n- [ClinicalTrials.gov - Huntington's Disease](https://clinicaltrials.gov/search?cond=Huntington+Disease)\n\n## References\n\n1. [Reiner & Deng, Huntington's disease: The corticostriatal circuit (2021)](https://doi.org/10.3233/JHD-200435)\n2. [Parent & Hazrati, Functional anatomy of the basal ganglia (1995)](https://doi.org/10.1016/0165-0173(94)00007-C)\n3. [Saudou & Humbert, The biology of huntingtin (2016)](https://doi.org/10.1016/j.neuron.2016.02.003)\n4. [Plotkin & Surmeier, Corticostriatal synaptic adaptations in HD (2015)](https://doi.org/10.1016/j.conb.2015.01.020)\n5. [Raymond et al., Pathophysiology of Huntington's disease (2014)](https://doi.org/10.1098/rstb.2013.0477)\n6. [Spires et al., Environmental enrichment in HD mouse models (2004)](https://doi.org/10.1523/JNEUROSCI.1658-03.2004)\n7. [Milnerwood & Raymond, Corticostriatal synaptic function in HD (2010)](https://doi.org/10.1016/j.pnpbp.2009.12.003)\n8. [Andre et al., Dopamine and glutamate in Huntington's disease (2010)](https://doi.org/10.1517/14728222.2010.487874)\n9. [Ferrante, Mouse models of Huntington's disease (2009)](https://doi.org/10.1016/j.bbadis.2009.04.001)\n10. [Ross & Tabrizi, Huntington's disease: From molecular pathogenesis to clinical treatment (2011)](https://doi.org/10.1016/S1474-4422(10)70245-3)",
  "entity_type": "mechanism"
}
  5. v1
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  "content_md": "## Overview\n\nCorticostriatal synaptic vulnerability is a hallmark feature of Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the [HTT](/genes/htt) gene encoding huntingtin protein. The corticostriatal pathway, which connects cortical neurons to the striatum, undergoes progressive degeneration that underlies many of the characteristic motor and cognitive symptoms of HD.\n\n## The Corticostriatal Pathway in Huntington's Disease\n\n### Anatomical Background\n\nThe corticostriatal pathway is one of the major excitatory input systems to the basal ganglia. Cortical layer 5 pyramidal neurons send dense glutamatergic projections to the striatum, where they synapse onto medium spiny neurons (MSNs), the principal output neurons of the striatum. This pathway is critical for motor initiation, habit formation, and procedural learning.\n\nIn Huntington's disease, both the cortical neurons that send projections and the striatal neurons that receive them undergo degeneration, leading to a \"dying-back\" pattern of neurodegeneration that begins at the synaptic terminals and progresses proximally toward the cell bodies.\n\n## Molecular Mechanisms of Synaptic Vulnerability\n\n### Mutant Huntingtin-Induced Synaptic Dysfunction\n\nThe mutant huntingtin protein (mHTT) exerts toxic effects on synapses through multiple mechanisms:\n\n#### 1. Loss of Normal Huntingtin Function\n\nWild-type huntingtin (wtHTT) is essential for:\n- Synaptic vesicle trafficking and neurotransmitter release\n- Dendritic spine maintenance and plasticity\n- Transcriptional regulation of synaptic proteins\n- Autophagy and clearance of synaptic debris\n\nThe mutation leads to loss of these protective functions, making synapses more vulnerable to stress and damage.\n\n#### 2. Toxic Gain-of-Function\n\nMutant huntingtin forms:\n- Aberrant protein aggregates that sequester essential synaptic proteins\n- Transcriptional dysregulation of synaptic genes\n- Disrupted mitochondrial function at synapses\n- Impaired proteostasis mechanisms\n\n#### 3. Excitotoxicity\n\nExcitotoxicity is a major contributor to corticostriatal vulnerability in HD:\n\n**Glutamate Receptor Dysfunction:**\n- NMDA receptor (NMDAR) hyperactivity contributes to calcium dysregulation\n- Altered AMPA receptor (AMPAR) trafficking reduces synaptic stability\n- Metabotropic glutamate receptors (mGluRs) show abnormal signaling\n\n**Calcium Homeostasis Disruption:**\n- Endoplasmic reticulum stress at synapses\n- Mitochondrial calcium overload\n- Activation of calcium-dependent degradative enzymes\n\n### Synaptic Protein Alterations in HD\n\n| Protein Category | Changes in HD | Functional Impact |\n|------------------|---------------|------------------|\n| Presynaptic proteins | Reduced synaptophysin, synaptobrevin | Impaired vesicle release |\n| Postsynaptic density | Altered PSD-95, Homer | Disrupted signaling scaffolds |\n| Ion channels | Cav1.2, Kv4.2 dysregulation | Abnormal excitability |\n| Neurotrophin receptors | TrkB signaling impairment | Reduced synaptic plasticity |\n\n## Cellular and Circuit-Level Changes\n\n### Medium Spiny Neuron Vulnerability\n\nMedium spiny neurons (MSNs), the primary target of corticostriatal inputs, show particular vulnerability in HD:\n\n#### Dendritic Spine Loss\n- Early loss of dendritic spines on MSNs precedes behavioral deficits\n- Spine loss is most pronounced on the distal dendrites where corticostriatal inputs terminate\n- This reflects the vulnerability of excitatory synapses specifically\n\n#### Synaptic Input Remodeling\n- Loss of corticostriatal excitatory inputs\n- Increased inhibitory inputs from local interneurons\n- Imbalance between excitation and inhibition\n\n#### Electrophysiological Changes\n- Resting membrane potential depolarization\n- Reduced input resistance\n- Abnormal firing patterns\n- Impaired long-term potentiation (LTP) and depression (LTD)\n\n### Cortical Neuron Degeneration\n\nThe cortical neurons that provide input to the striatum also degenerate:\n- Layer 5 pyramidal neurons show reduced corticostriatal axon integrity\n- Cortical hyperexcitability precedes striatal degeneration\n- Decreased brain-derived neurotrophic factor (BDNF) transport from cortex to striatum\n\n## Stages of Corticostriatal Degeneration\n\n### Preclinical/Presymptomatic Stage\n- Subtle synaptic plasticity deficits\n- Early dendritic spine changes\n- Normal motor behavior\n\n### Early HD\n- Significant spine loss on MSNs\n- Corticostriatal connectivity reduction\n- Minor motor and cognitive changes\n\n### Moderate HD\n- Marked corticostriatal synaptic loss\n- Severe behavioral symptoms\n- Neuronal atrophy begins\n\n### Advanced HD\n- Extensive degeneration of corticostriatal pathway\n- Severe motor and cognitive impairment\n- Widespread brain atrophy\n\n## Therapeutic Implications\n\n### Targeting Corticostriatal Synapses\n\n#### 1. Synaptic Protection\n- NMDA receptor modulators to reduce excitotoxicity\n- Calcium channel blockers to protect synaptic calcium homeostasis\n- Synaptic protein stabilizers\n\n#### 2. Restoring Synaptic Function\n- BDNF mimetics to support synaptic plasticity\n- AMPA receptor positive allosteric modulators\n- Synaptic vesicle cycle enhancers\n\n#### 3. Disease-Modifying Approaches\n- Huntingtin-lowering therapies (ASOs, CRISPR)\n- Autophagy enhancers to clear toxic protein aggregates\n- Transcriptional regulators to restore synaptic gene expression\n\n### Clinical Trial Implications\n\nCorticostriatal synaptic integrity is increasingly used as a biomarker:\n- PET imaging of synaptic vesicle protein 2A (SV2A)\n- Cerebrospinal fluid synaptic biomarkers (neurogranin, SNAP-25)\n- Structural MRI measures of striatal volume\n\n## Pathway Diagram: Corticostriatal Synaptic Vulnerability\n\n```mermaid\nflowchart TD\n    A[\"mHTT Expression\"] --> B[\"Cortical Neurons\"]\n    A --> C[\"Striatal Medium Spiny Neurons\"]\n\n    B --> D[\"Synaptic Dysfunction\"]\n    C --> D\n\n    D --> E[\"Glutamate Excitotoxicity\"]\n    D --> F[\"NMDA Receptor Dysregulation\"]\n    D --> G[\"Cav1.2 Channel Dysfunction\"]\n\n    E --> H[\"Calcium Dysregulation\"]\n    F --> H\n    G --> H\n\n    H --> I[\"Mitochondrial Permeability Transition\"]\n    I --> J[\"ATP Depletion\"]\n\n    J --> K[\"Striatal Neuron Death\"]\n    K --> L[\"Huntington's Disease Phenotype\"]\n\n    style A fill:#1a0a1f,stroke:#333\n    style L fill:#3e2200,stroke:#333\n```\n\n## See Also\n\n- [Huntington's Disease](/diseases/huntingtons)\n- [Huntingtin Protein](/proteins/huntingtin-protein)\n- [Medium Spiny Neurons](/cell-types/medium-spiny-neurons)\n- [Excitotoxicity in Neurodegeneration](/mechanisms/excitotoxicity)\n- [Huntington's CAG Repeat Expansion](/mechanisms/huntingtons-cag-repeat-expansion)\n- [BDNF Signaling in Neurodegeneration](/mechanisms/bdnf-signaling-neurodegeneration)\n\n## External Links\n\n- [Huntington's Disease Society of America](https://hdsa.org/)\n- [CHDI Foundation](https://chdifoundation.org/)\n- [NIH - Huntington's Disease Information](https://www.ninds.nih.gov/Disorders/All-Disorders/Huntingtons-Disease-Information-Page)\n- [ClinicalTrials.gov - Huntington's Disease](https://clinicaltrials.gov/search?cond=Huntington+Disease)\n\n## References\n\n1. [Reiner & Deng, Huntington's disease: The corticostriatal circuit (2021)](https://doi.org/10.3233/JHD-200435)\n2. [Parent & Hazrati, Functional anatomy of the basal ganglia (1995)](https://doi.org/10.1016/0165-0173(94)00007-C)\n3. [Saudou & Humbert, The biology of huntingtin (2016)](https://doi.org/10.1016/j.neuron.2016.02.003)\n4. [Plotkin & Surmeier, Corticostriatal synaptic adaptations in HD (2015)](https://doi.org/10.1016/j.conb.2015.01.020)\n5. [Raymond et al., Pathophysiology of Huntington's disease (2014)](https://doi.org/10.1098/rstb.2013.0477)\n6. [Spires et al., Environmental enrichment in HD mouse models (2004)](https://doi.org/10.1523/JNEUROSCI.1658-03.2004)\n7. [Milnerwood & Raymond, Corticostriatal synaptic function in HD (2010)](https://doi.org/10.1016/j.pnpbp.2009.12.003)\n8. [Andre et al., Dopamine and glutamate in Huntington's disease (2010)](https://doi.org/10.1517/14728222.2010.487874)\n9. [Ferrante, Mouse models of Huntington's disease (2009)](https://doi.org/10.1016/j.bbadis.2009.04.001)\n10. [Ross & Tabrizi, Huntington's disease: From molecular pathogenesis to clinical treatment (2011)](https://doi.org/10.1016/S1474-4422(10)70245-3)",
  "entity_type": "mechanism"
}