Cell death plays a central role in the progression of neurodegenerative disorders, including Huntington’s disease, where widespread neuronal loss ultimately leads to functional decline. Although motor failure is the most apparent symptom of Huntington’s disease, cognitive disturbances often emerge earlier, reflecting an initial phase where neuronal and synaptic dysfunction precede outright degeneration. This suggests that subtle disruptions in neuronal communication come before and potentially drive subsequent stages of disease pathology. Recent studies in mouse models of Huntington’s disease have demonstrated that pharmacological interventions targeting these early functional abnormalities can reverse neuronal dysfunction and delay the onset of neurodegeneration.1,2 These findings underscore the importance of diagnosis and intervention for early molecular and cellular disturbances, offering hope not only for modifying the inevitable course of Huntington’s but also for informing therapeutic strategies in other neurodegenerative diseases that are characterized by progressive neuronal loss.3
Huntington’s disease is caused by a CAG repeat expansion in the huntingtin (Htt) gene, leading to production of a mutant protein (mHtt) that is widely expressed but selectively toxic to certain neurons, particularly striatal medium spiny neurons (MSNs). This selective vulnerability results from intrinsic neuronal factors, with glutamate excitotoxicity and metabolic stress contributing to MSN degeneration. Genetic murine models have revealed that early disturbances caused by mHtt, such as those correlating with repeat length, may drive neurotoxicity and play a key role in disease progression.4
Before notable cell death, Huntington’s disease causes disruptions in neuronal and synaptic protein expression, including reduced levels of neurotransmitters, receptors, and related mRNAs. MSN neuropeptide stores are diminished, as are dopamine, glutamate, and endocannabinoid receptors. These transcriptional changes are conserved across mouse models, regardless of disease severity, indicating these gene expression disruptions are a fundamental feature of the disease. In a landmark 2001 study from Italy, researchers demonstrated the wild-type huntingtin gene upregulates transcription of brain-derived neurotrophic factor (BDNF), a pro-survival factor critical for healthy MSNs. The beneficial activity of wild-type huntingtin is lost when the protein is mutated, resulting in decreased production of cortical BDNF, and subsequently, MSNs. Striatal MSNs do not produce their own BDNF and rely on its delivery from cortical afferents.5 Additionally, cAMP levels are reduced in mouse models of Huntington’s disease, as are phosphorylation and activation of CREB, the cAMP response element binding protein. In healthy systems, transcription of CREB is mediated by synaptic NMDA receptors and plays a key role in synaptic plasticity, mitochondrial dysfunction, and cell survival.3
Altered synaptic transmission and impaired neuroplasticity are other critical contributors to the pathogenesis of Huntington’s disease. In the early stages, specific cortical inputs release excess glutamate onto striatal neurons, causing excitotoxicity, calcium overload, and neuronal stress.6 This can lead to synaptic damage and dendritic spine loss, culminating in reduced glutaminergic transmission in later stages of the disease. The decline in synaptic activity impairs neuronal plasticity and BDNF signaling, driving eventual MSN loss and motor deficits.3 Evidence suggests lasting alternations to synaptic connectivity are produced by changes in synaptic activity, which mimic long-term potentiation and depression (LTP and LTD). In murine models of Huntington’s disease, disruptions to LTP and LTD are among the neuronal changes that precede motor dysfunction.
There is also a significant link between the NMDA receptor subunit NR2B and the effects of the mutated huntingtin gene. NMDA receptor currents are larger in heterologous cells co-expressing mHtt and NR2B but not in cells co-expressing mHtt and NR2A.7 Excessive NMDA receptor activity is neurotoxic, since it increases calcium influx, which leads to dysregulation of gene transcription, protein synthesis, and neuronal survival.3
Huntington’s disease progresses through a cascade of early synaptic and molecular dysfunctions that precede and contribute to subsequent neuronal death. Disruptions in glutamatergic signaling, BDNF transport, and NMDA receptor activity play central roles in weakening striatal neurons. Understanding and targeting these early synaptic pathophysiological changes offers a promising path for therapeutic intervention before irreversible neurodegeneration.

References

1. Milnerwood, Austen J., et al. Early Increase in Extrasynaptic NMDA Receptor Signaling and Expression Contributes to Phenotype Onset in Huntington’s Disease Mice. Neuron, 65(2), 2010, 178–190. https://doi.org/10.1016/j.neuron.2010.01.008
2. Okamoto, Shu-ichi, et al. Balance between Synaptic versus Extrasynaptic NMDA Receptor Activity Influences Inclusions and Neurotoxicity of Mutant Huntingtin. Nature Medicine, 15(12), 2009, 1407–1413. https://doi.org/10.1038/nm.2056
3. Milnerwood, Austen J., and Lynn A. Raymond. Early Synaptic Pathophysiology in Neurodegeneration: Insights from Huntington’s Disease. Trends in Neurosciences, 33(11), 2010, 513–523. https://doi.org/10.1016/j.tins.2010.08.002
4. Bates G., Harper P.S., Jones L., Huntington’s Disease. Oxford University Press; 2002
5. Zuccato C., Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington’s Disease. Science. 2001;293(5529):493-498. https://doi.org/10.1126/science.1059581
6. Stack E.C., A. Dedeoglu, Smith K.M., et al. Neuroprotective Effects of Synaptic Modulation in Huntington’s Disease R6/2 Mice. The Journal of Neuroscience. 2007;27(47):12908-12915. https://doi.org/10.1523/jneurosci.4318-07.2007
7. Chen N., Luo T., Wellington C., et al. Subtype-Specific Enhancement of NMDA Receptor Currents by Mutant Huntingtin. Journal of Neurochemistry. 2008;72(5):1890-1898. https://doi.org/10.1046/j.1471-4159.1999.0721890.x