Role of Excitatory Amino Acid Carrier 1 (EAAC1) in Neuronal Death and Neurogenesis After Ischemic Stroke

Abstract

Although there have been substantial advances in knowledge regarding the mechanisms of neuron death after stroke, effective therapeutic measures for stroke are still insufficient. Excitatory amino acid carrier 1 (EAAC1) is a type of neuronal glutamate transporter and considered to have an additional action involving the neuronal uptake of cysteine, which acts as a crucial substrate for glutathione synthesis. Previously, our lab demonstrated that genetic deletion of EAAC1 leads to decreased neuronal glutathione synthesis, increased oxidative stress, and subsequent cognitive impairment. Therefore, we hypothesized that reduced neuronal transport of cysteine due to deletion of the EAAC1 gene might exacerbate neuronal injury and impair adult neurogenesis in the hippocampus after transient cerebral ischemia. EAAC1 gene deletion profoundly increased ischemia-induced neuronal death by decreasing the antioxidant capacity. In addition, genetic deletion of EAAC1 also decreased the overall neurogenesis processes, such as cell proliferation, differentiation, and survival, after cerebral ischemia. These studies strongly support our hypothesis that EAAC1 is crucial for the survival of newly generated neurons, as well as mature neurons, in both physiological and pathological conditions. Here, we present a comprehensive review of the role of EAAC1 in neuronal death and neurogenesis induced by ischemic stroke, focusing on its potential cellular and molecular mechanisms.

Revealing the contribution of astrocytes to glutamatergic neuronal transmission

“…Neurons in the rat cerebral cortex, hippocampus, cerebellum, and spinal cord express the EAAC1 transporters (Kanai et al, 1995 ; Shashidharan et al, 1997 ). Interestingly, this transporter is mainly involved in anion conductance and uptake of cysteine, a precursor of glutathione synthesis (Lee et al, 2020 ). EAAT4 is highly expressed in cerebellar Purkinje cells (Magi et al, 2019 ).…”

Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

“…These malignant characteristics were weakened to a great degree after long-term treatment with AMPA receptor antagonists and calpain inhibitors, reflecting that excessive activation of AMPA and intracellular calcium overload after glutamate transporter deficiency are the pathological mechanisms that mediate motoneuron death [ 178 ]. In addition, Minwoo Lee [ 179 ] et al proved that EAAT3 knockout could also aggravate neuronal death after tMCAO and inhibit the proliferation and repair of hippocampal cells themselves.…”

“…In particular, neuron EAAT3 is thought to be involved in the extra uptake of cysteine and is responsible for the conversion of glutamate into reactive oxygen species (ROS) scavenger glutathione [ 181 ]. It has been confirmed that the aggravation of ischemic injury caused by EAAT3 deletion is mainly attributed to the decrease in glutathione synthesis and the increase in oxidative stress [ 179 ]. Other studies have also shown that drugs promoting the glutamate–glutathione metabolic cycle can reduce glutamate and synaptic excitability, thus having a detoxification effect [ 182 ].…”

The Role of NADPH Oxidase in Neuronal Death and Neurogenesis after Acute Neurological Disorders

“…All NSCs exist in the heterogeneous state, which undergoes both symmetric division (functional self-renewal) or asymmetric division (one mature to neuron). In both niches, NSCs migrate to certain brain regions and differentiate to immature neurons, showing hyperexcitability and increased susceptibility to synaptic inputs [ 74 ]. The process of neurogenesis in SGZ begins with glial fibrillary acidic protein (GFAP)-positive radial glial-like NSCs (type I cells) in SGZ turning into GFAP-negative progenitors (type II cells) in the granular cell layer [ 75 , 76 , 77 ].…”