From the Guidelines
The neurotransmitter primarily depleted in Huntington disease is gamma-aminobutyric acid (GABA). This depletion occurs particularly in the basal ganglia, especially the striatum, which includes the caudate nucleus and putamen, as a result of the loss of GABAergic medium spiny neurons, particularly in the striatum and cortex 1. GABA is the main inhibitory neurotransmitter in the brain, and its reduction leads to excessive neuronal activity and the characteristic involuntary movements (chorea) seen in Huntington's disease. The disease involves progressive degeneration of GABAergic medium spiny neurons, which make up about 95% of neurons in the striatum. Some key points to consider include:
- The genetic basis of the disease is an abnormally increased number of CAG repeats in the huntingtin gene on the short arm of chromosome 4 1
- Abnormal aggregates of the huntingtin protein accumulate in the brain and impair the function of a variety of transcription factors, ultimately leading to the loss of GABAergic medium spiny neurons 1
- While GABA is the primary neurotransmitter affected, Huntington's disease also involves disruptions in other neurotransmitter systems, including glutamate, dopamine, and acetylcholine. The imbalance between these neurotransmitter systems contributes to the complex motor, cognitive, and psychiatric symptoms that characterize this hereditary neurodegenerative disorder.
From the Research
Neurotransmitter Depletion in Huntington Disease
The primary neurotransmitter depleted in Huntington disease is a subject of ongoing research. Key findings include:
- Decreased concentrations of the neuroinhibitory transmitter gamma aminobutyric acid (GABA) have been found in patients with Huntington's disease 2.
- Alterations in dopaminergic neurotransmission have also been observed, with biphasic changes in dopamine (DA) neurotransmission throughout the progression of the disease 3.
- In the early stages of Huntington's disease, DA neurotransmission is increased, leading to hyperkinetic movements, while in the late stages, DA deficits produce hypokinesia 3.
- GABAergic systems have been found to be impaired in Huntington's disease, with changes in the expression of GABAA receptors 4.
- Dopaminergic dysfunction has been linked to the motor impairments characteristic of Huntington's disease, and anti-dopaminergic agents are commonly used to treat these symptoms 5.