The Role of Excitotoxicity in Essential Tremor Cerebellum

2014, IETF Funded Research Archives

The cause and development of ET remains poorly understood. Functional imaging studies show cerebellar abnormalities in patients living with ET. The goal of this research is to investigate the role of excitotoxicity in the postmortem essential tremor cerebellum. Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters. It has been a suggested approach for ET, however there has yet to be any direct evidence that excitotoxicity plays a role in ET patients. Researchers propose to test this hypothesis by examining the number of excitatory synapses (structures that permit a neuron to pass an electrical or chemical signal to another cell) and the levels of excitotoxicity markers in the ET cerebellum. This will be the key step to understanding the process of cerebellar degenerative process in ET. The study will be conducted by Dr. Sheng-Han Kuo at the Essential Tremor Centralized Brain Repository, New York Brain Bank, Columbia University, New York.

Results from The Role of Excitotoxicity in Essential Tremor Cerebellum

Decreased EAAT2 Protein Expression in the Essential Tremor Cerebellar Cortex

Essential tremor (ET) is a prevalent neurological disease marked by a persistent action tremor in the arms. It has a strong genetic component, as ET patients often have a family history of tremor, and twins with ET are highly concordant for disease status. Recently, polymorphisms (the occurrence of two or more genetically determined characteristics or traits in a certain population) in the solute carrier family 1 (glial high affinity glutamate transporter), member 2 (SLC1A2) gene have emerged as a potential genetic risk factor for ET in a genome-wide association study in Europe. While this association was subsequently confirmed in two Asian cohorts, another study did not show an association, and a meta-analysis revealed conflicting results. Given this evolving picture, the SLC1A2 gene remains of considerable interest. The SLC1A2 gene encodes excitatory amino acid transporter 2 (EAAT2), which is a protein that is critical for maintaining glutamate levels in the synaptic cleft in the adult brain.

Glutamatergic synapses are the major excitatory synapses in the brain, and brain glutamate levels are exquisitely controlled. Excessive extracellular glutamate, due to over-excitation of neurons or failure of glutamate recycling, can lead to mitochondrial dysfunction and subsequent neuronal death. This mechanism of “excitotocity” has been implicated to be of potential patho-mechanistic importance in epilepsy, stroke, and amyotrophic lateral sclerosis. Extracellular glutamate levels are mainly

regulated by a family of glutamate transporters, the excitatory amino-acid transporters (EAATs), which in the central nervous system comprise five subtypes (EAAT1 – 5). Both EAAT1 and EAAT2 are expressed predominantly in astrocytes, the major cell type responsible for glutamate uptake. EAAT1 is expressed during development and also in adulthood, whereas EAAT2 is the main glutamate transporter in adult brain, responsible for over 90% of total glutamate uptake.

Clinical and neuroimaging evidence has pointed to the importance of the cerebellum in the development of ET. Postmortem studies have revealed a broad range of structural changes in the cerebellum in ET. These include Purkinje cell (PC) loss in some studies, but not in the others. One hypothesized mechanism for ET is that it is a disorder of over-excitation of glutamatergic olivo-cerebellar climbing fibers, which results in excitotoxic damage to PCs. Alterations in EAAT levels in the cerebellar cortex could result in a breakdown in normal extracellular glutamate homeostasis (environment), enhancing vulnerability to excitotoxic damage. Since EAAT1 and EAAT2 are the two major glutamate transporters in the cerebellar cortex, we systematically investigated the expression level and immunohistochemical cellular localization of these two proteins in the postmortem cerebellum of ET cases vs. controls.

This study showed that excitatory amino acid transporter 2 (EAAT2) levels (which is a protein that is critical for maintaining glutamate levels in the synaptic cleft in the adult brain) were significantly decreased in the essential tremor cerebellar cortex, in contrast to similar levels of EAAT1 levels between ET cases and controls. (Glutamate is the predominant excitatory neurotransmitter in the brain.) ET brains might be more vulnerable to excitotoxic damage than those of controls. Further study of the relationship between astrocytes (cells) and Purkinje cell (PC) injury might be central to understanding the development of ET. Medications that increase EAAT2, such as beta-lactam antibiotics, might be candidates for therapy for essential tremor. (Beta-lactum antibiotics offer neuroprotection by increasing transporter expression.)