Mechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease

doi:10.1016/j.drudis.2014.02.006

Drug Discovery Today

Volume 19, Issue 7, July 2014, Pages 990-996

https://doi.org/10.1016/j.drudis.2014.02.006 Get rights and content

Highlights

•
Indirect pathway striatal neurons are most vulnerable.
•
Pro-survival trophic support by BDNF is reduced.
•
Endocannabinoid mediated signaling is disrupted.
•
Dopamine release is imbalanced.
•
Excessive NMDAR signaling promotes cell death.

Huntington's disease (HD) is an inherited neurodegenerative disorder of movement, mood and cognition, caused by a polyglutamine expansion in the huntingtin (Htt) protein. Genetic mouse models of HD, along with improved imaging techniques in humans at risk of, or affected by, HD, have advanced understanding of the cellular and/or molecular mechanisms underlying its pathogenesis. The striatum begins to degenerate before other brain areas, and altered activity at corticostriatal synapses contributes to an imbalance in survival versus death signaling pathways in this brain region. Striatal projection neurons of the indirect pathway are most vulnerable, and their dysfunction contributes to motor symptoms at early stages of the disease. Mutant Htt expression changes striatal excitatory synaptic activity by decreasing glutamate uptake and increasing signaling at N-methyl-d-aspartate receptors (NMDAR). A variety of studies indicate that reduced brain-derived neurotrophic factor (BDNF) transcription, transport and signaling contribute importantly to striatal neuronal dysfunction and degeneration in HD. Striatal dopamine and endocannabinoid signaling are also altered and progressively become dysfunctional. Changes at striatal neurons vary with the stage of disease and clinical symptoms. Therapeutics targeting multiple neurotransmitter signaling systems could support physiological synaptic function and delay disease onset.

Section snippets

Neuropathology of the cortex and striatum

Htt is expressed throughout the body and is required for normal embryonic development [7]. It has a physiological role in intracellular processes, such as gene transcription, protein trafficking and mitochondrial function. mHtt is toxic to cells and forms aggregates in the nucleus and cytoplasm [8]. Although mHtt is expressed throughout the brain and body, postmortem studies show that progressive degeneration of neurons occurs mainly in the caudate-putamen (striatum) and cortex [9]. In vivo

Pathway specificity

The striatum and other nuclei of the basal ganglia provide contextual information for motor control and action selection 13, 14. The striatum itself processes massive input from the cortex, along with input from the thalamus and midbrain, to coordinate goal-directed behavior and learning. Striatal output is complex, but classically simplified into two complementary pathways with different functional outcomes (Fig. 1). The ‘direct’ pathway from the striatum promotes cortical action selection and

Dopamine

DA released by afferents to the striatum from the substantia nigra pars compacta has opposing effects on dSPN and iSPN and mediates long-term synaptic changes. DA has higher affinity at D2 compared with D1 receptors, and signaling depends on the concentration of extracellular DA. Tonic low levels of DA can activate D2 and reduce iSPN activity. By contrast, DA released in physiological bursts, activates D1 and positively modulates the direct pathway [21]. This suggests that a change in tonic DA

Glutamate

Excitotoxicity in the striatum occurs when excessive glutamatergic signaling and disrupted intracellular calcium levels lead to mitochondrial energy failure and cell death. In HD, changes in glutamate release, uptake and postsynaptic signaling converge to promote the excitotoxicity of SPN. Increased glutamate release occurs at early stages of HD, followed by the loss of glutamatergic terminals in fully symptomatic HD, indicating a disconnection of the cortex and striatum [6]. Elevated glutamate

NMDAR

Overactivation of NMDARs can render neurons susceptible to excitotoxicity because of high Ca²⁺ permeability and slow deactivation, which results in intracellular Ca²⁺ overload. Injection of the selective NMDAR agonist quinolinic acid in rodents mimics HD by triggering the loss of striatal SPN [32]. Systemic administration of the mitochondrial toxin 3-nitropropionic acid also causes striatal lesions that can be rescued by NMDAR antagonists [33]. The selective loss of striatal SPN over other cell

BDNF

BDNF is a growth factor released by neurons that supports neurite growth and spine formation in the adult brain [54]. Striatal neurons are dependent on BDNF release by axons from other brain areas. Increasing evidence points to alterations in BDNF and its tyrosine kinase receptor, TrkB, on SPN as a mechanism of early dysfunction in HD.

In the mouse, loss of BDNF itself results in neuropathology and symptoms similar to HD. Ablation of BDNF from the cortex and substantia nigra depletes BDNF in the

Endocannabinoids

Endogenous cannabinoids (endocannabinoids, eCBs) are lipophilic neuromodulators produced on demand in neurons and act at G protein-coupled cannabinoid receptors, CB₁ and CB₂. CB₁ is presynaptic and inhibits neurotransmitter release. Transient eCB signaling provides activity-dependent retrograde feedback at synapses and mediates LTD [21]. Endocannabinoid involvement in cognitive processes was recently extended by the influence of CB₁ localized on astrocytes [68] and mitochondria [69].

Microglia

Concluding remarks

In HD, multiple factors impinge on striatal projection neurons, rendering them susceptible to dysfunction and degeneration. Increases in DA acting at D2 receptors, as well as enhanced interneuron activity, combine to reduce output of the indirect pathway, resulting in involuntary movements. Reduced BDNF and CB₁ impair the ability of striatal neurons to modify synaptic activity. Impaired glutamate uptake by astrocytes and increased extrasynaptic NMDAR signaling might suppress plasticity and

Acknowledgments

This work was supported by grants to LAR from the Canadian Institutes of Health Research (MOP-12699 and GPG 102165) and the Cure Huntington Disease Initiative (CHDI) Foundation.

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ReviewPost screenMechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease

Highlights

Section snippets

Neuropathology of the cortex and striatum

Pathway specificity

Dopamine

Glutamate

NMDAR

BDNF

Endocannabinoids

Concluding remarks

Acknowledgments

Biol. Psychiatry

Lancet Neurol.

Neuroscience

Cell

Exp. Neurol.

Trends Neurosci.

Neuron

Basal Ganglia

Neurobiol. Dis.

Brain Res.

Neuron

Neuroscience

Neuron

Neurobiol. Dis.

Neurobiol. Dis.

Parkinsonism Relat. Disord.

Lancet Neurol.

Cell

Neurobiol. Dis.

Neuron

Neuroscience

Neurobiol. Dis.

Pharmacol. Ther.

A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes

Cell

Detection of Huntington's disease decades before diagnosis: the Predict–HD study

J. Neurol. Neurosurg. Psychiatry

Refining the diagnosis of Huntington disease: the PREDICT-HD study

Front. Aging Neurosci.

Huntington disease

J. Neuropathol. Exp. Neurol.

Optogenetic insights into striatal function and behavior

Behav. Brain Res.

Dysregulated neuronal activity patterns implicate corticostriatal circuit dysfunction in multiple rodent models of Huntington's disease

Front. Syst. Neurosci.

Alterations in striatal synaptic transmission are consistent across genetic mouse models of Huntington's disease

ASN Neuro.

Brain networks in Huntington disease

J. Clin. Invest.

Dichotomous anatomical properties of adult striatal medium spiny neurons

J. Neurosci.

Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value

Nat. Neurosci.

Multiple sources of striatal inhibition are differentially affected in Huntington's disease mouse models

J. Neurosci.

Dopaminergic neurons inhibit striatal output through non-canonical release of GABA

Nature

Altered balance of activity in the striatal direct and indirect pathways in mouse models of Huntington's disease

Front. Syst. Neurosci.

Modulation of striatal projection systems by dopamine

Annu. Rev. Neurosci.

Role of tetrabenazine for Huntington's disease-associated chorea

Ann. Pharmacother.

Genetic mouse models of Huntington's disease: focus on electrophysiological mechanisms

ASN Neuro.

Review
Post screen
Mechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease