Targeting glutamate transporter-1 in neurological diseases

The accumulation of glutamate in the brain is toxic to neurons and therefore must be tightly regulated. Expressed predominantly on astrocytes, glutamate transporter-1 (GLT1) is responsible for the majority of glutamate clearance from the extracellular space in the forebrain (Figure 1). Due to its importance in glutamate homeostasis and consequently maintaining neuronal health, dysregulation of GLT1 has severe consequences. In fact, GLT1 is found to be downregulated or dysfunctional in several neurological disorders, including epilepsy, amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). Exactly how GLT1 is regulated, however, is an important consideration in each of these diseases. Epilepsy is comprised of a group of disorders characterized by the unpredictable occurrence of seizures. One of the most common rodent models of epilepsy is the intrahippocampal kainic acid (IHKA) model. Specifically, mice are given a unilateral injection of kainic acid into the dorsal hippocampus. After a prolonged latency period, rodents begin to have spontaneous seizures and are considered epileptic. During that latency period, the brain is transitioning from a healthy one into an epileptic one, a process known as epileptogenesis. Dorsal GLT1 protein expression is downregulated in both hippocampi at time points within the latency period [3]. GLT1 mRNA, on the other hand, is largely unaffected suggesting that GLT1 is regulated at the post-transcriptional level. The fact that GLT1 is downregulated prior to the onset of spontaneous seizures suggests that GLT1 is a key component of the epileptogenic process and therefore is an excellent antiepileptic therapeutic target. If downregulation of GLT1 could be prevented, it is possible that the development of epilepsy could be prevented altogether. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that causes death of motor neurons. Patients exhibit a gradual weakening and wasting of muscles. Originally created in 1994, a common model of ALS is a transgenic mouse line containing a mutation in the Cu2+, Zn2+ superoxide dismutase (SOD-1) enzyme. Specifically, a point mutation at amino acid position 93 (G to A) leads to adult-onset neurodegeneration of motor neurons, progressive motor deficits, and eventual paralysis. Similar to what was observed in the IHKA epilepsy model, focal loss of GLT1 expression was observed before the onset of disease hallmarks (motor neuron degeneration) and continues well after the onset of symptoms [2]. Furthermore, an early study found no change in GLT1 mRNA in the motor cortex of patients with ALS suggesting that GLT1 abnormalities are introduced at the post-translational level [1]. Alzheimer’s disease (AD) is also a progressive neurodegenerative disease but it is characterized by memory impairments and progressive dementia. Hallmark of this disease include abnormal deposits of amyloid beta Editorial