Regulation of NRG-1-ErbB4 signaling and neuroprotection by exogenous neuregulin-1 in a mouse model of epilepsy.

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy. Dysregulation of glutamate transporters has been a common finding across animal models of epilepsy and in patients with TLE. In this study, we investigate NRG-1/ErbB4 signaling in epileptogenesis and the neuroprotective effects of NRG-1 treatment in a mouse model of temporal lobe epilepsy. Using immunohistochemistry, we report the first evidence for NRG-1/ErbB4-dependent selective upregulation of glutamate transporter EAAC1 and bihemispheric neuroprotection by exogeneous NRG-1 in the intrahippocampal kainic acid (IHKA) model of TLE. Our findings provide evidence that dysregulation of glutamate transporter EAAC1 contributes to the development of epilepsy and can be therapeutically targeted to reduce neuronal death following IHKA-induced status epilepticus (SE).

Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy.

Astrocytic glutamate transporters are crucial for glutamate homeostasis in the brain, and dysregulation of these transporters can contribute to the development of epilepsy. Glutamate transporter-1 (GLT-1) is responsible for the majority of glutamate uptake in the dorsal forebrain and has been shown to be reduced at epileptic foci in patients and preclinical models of temporal lobe epilepsy (TLE). Current antiepileptic drugs (AEDs) work primarily by targeting neurons directly through suppression of excitatory neurotransmission or enhancement of inhibitory neurotransmission, which can lead to both behavioral and psychiatric side effects. This study investigates the therapeutic capacity of astrocyte-specific AAV-mediated GLT-1 expression in the intrahippocampal kainic acid (IHKA) model of TLE. In this study, we used Western blot analysis, immunohistochemistry, and long-term-video EEG monitoring to demonstrate that cell-type-specific upregulation of GLT-1 in astrocytes is neuroprotective at early time points during epileptogenesis, reduces seizure frequency and total time spent in seizures, and eliminates large behavioral seizures in the IHKA model of epilepsy. Our findings suggest that targeting glutamate uptake is a promising therapeutic strategy for the treatment of epilepsy.

Astrocyte Glutamate Uptake and Signaling as Novel Targets for Antiepileptogenic Therapy.

Astrocytes regulate and respond to extracellular glutamate levels in the central nervous system (CNS) via the Na+-dependent glutamate transporters glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST) and the metabotropic glutamate receptors (mGluR) 3 and mGluR5. Both impaired astrocytic glutamate clearance and changes in metabotropic glutamate signaling could contribute to the development of epilepsy. Dysregulation of astrocytic glutamate transporters, GLT-1 and GLAST, is a common finding across patients and preclinical seizure models. Astrocytic metabotropic glutamate receptors, particularly mGluR5, have been shown to be dysregulated in both humans and animal models of temporal lobe epilepsy (TLE). In this review, we synthesize the available evidence regarding astrocytic glutamate homeostasis and astrocytic mGluRs in the development of epilepsy. Modulation of astrocyte glutamate uptake and/or mGluR activation could lead to novel glial therapeutics for epilepsy.

Post-translational Regulation of GLT-1 in Neurological Diseases and Its Potential as an Effective Therapeutic Target.

Glutamate transporter-1 (GLT-1) is a Na+-dependent transporter that plays a key role in glutamate homeostasis by removing excess glutamate in the central nervous system (CNS). GLT-1 dysregulation occurs in various neurological diseases including Huntington's disease (HD), Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and epilepsy. Downregulation or dysfunction of GLT-1 has been a common finding across these diseases but how this occurs is still under investigation. This review aims to highlight post-translational regulation of GLT-1 which leads to its downregulation including sumoylation, palmitoylation, nitrosylation, ubiquitination, and subcellular localization. Various therapeutic interventions to restore GLT-1, their proposed mechanism of action and functional effects will be examined as potential treatments to attenuate the neurological symptoms associated with loss or downregulation of GLT-1.

Regulation of Synaptosomal GLT-1 and GLAST during Epileptogenesis.

Astrocytes regulate extracellular glutamate homeostasis in the central nervous system through the Na+-dependent glutamate transporters glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST). Impaired astrocyte glutamate uptake could contribute to the development of epilepsy but the regulation of glutamate transporters in epilepsy is not well understood. In this study, we investigate the expression of GLT-1 and GLAST in the mouse intrahippocampal kainic acid (IHKA) model of temporal lobe epilepsy (TLE). We used immunohistochemistry, synaptosomal fractionation and Western blot analysis at 1, 3, 7 and 30 days post-IHKA induced status epilepticus (SE) to examine changes in GLT-1 and GLAST immunoreactivity and synaptosomal expression during the development of epilepsy. We found a significant upregulation in GLT-1 immunoreactivity at 1 and 3 days post-IHKA in the ipsilateral dorsal hippocampus. However, GLT-1 immunoreactivity and synaptosomal protein levels were significantly downregulated at 7 days post-IHKA in the ipsilateral hippocampus, a time point corresponding to the onset of spontaneous seizures in this model. GLAST immunoreactivity was increased in specific layers at 1 and 3 days post-IHKA in the ipsilateral hippocampus. GLAST synaptosomal protein levels were significantly elevated at 30 days compared to 7 days post-IHKA in the ipsilateral hippocampus. Our findings suggest that astrocytic glutamate transporter dysregulation could contribute to the development of epilepsy.