ReviewPost screenMechanisms of synaptic dysfunction and excitotoxicity in Huntington's disease
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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2023, Neurobiology of DiseaseCitation Excerpt :In particular, the reduced abundance of the neuronal-specific DHA-containing PS (44:12) (Guo et al., 2007) in the CA1 subfield of 12-week-old HD mice may contribute to the loss of cognitive function and long-term memory in HD (Giralt et al., 2012a; Ransome et al., 2012b; Giralt et al., 2012b), as this lipid is known to play a significant role in improving memory and cognitive abilities in elderly subjects with mild cognitive impairments (Vakhapova et al., 2014; Yurko-Mauro et al., 2010). Furthermore, the reduced abundance of GM1 observed in the CA1 and CA3 subfield of 16-week-old HD mice may contribute to glutamate excitotoxicity reported in HD mice hippocampi (Sepers and Raymond, 2014), as exogenous addition of GM1 has been shown to enhance neuronal survival by providing protection from glutamate excitability in primary neuronal cultures (Favaron et al., 1988). The dentate gyrus showed relatively fewer reductions in lipid abundances compared to CA1 and CA3 sub-fields in 12-week-old HD mice, with the most notable changes observed in the neuronal cell body-enriched PI and axonal-enriched PS lipid classes.
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