Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Abstract

The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

Neuronal mechanisms of epileptogenesis

“…Genetic mutations enhancing structural and functional alterations of key proteins including pre-synaptic complexes (Toader et al, 2013) and potassium channels (D'Adamo et al, 2013) are also related to the occurrence of epileptic disorders. Consistently with these findings obtained in genetic animal models of epilepsy, studies conducted in animal models of acquired epilepsy addressed the critical role of vesicular neurotransmitters transporters (VNTs) (Van Liefferinge et al, 2013) and non-neuronal potassium channel (Kir4.1) (Nagao et al, 2013) expression during epileptogenesis.…”

Altered vesicular glutamate transporter expression in human temporal lobe epilepsy with hippocampal sclerosis

“…Collectively, additional evidence has been found to support a possible involvement of VGLUTs in TLE, but still more and better experimental tools, such as specific inhibitors, are required (for review see [34]). Finally, it should be mentioned that antiepileptic drug treatment might affect VGLUT expression.…”

“…Several studies have investigated, VGLUT1 and VGLUT2 mRNA and/or protein levels in distinct animal models of epilepsy (for review see [34]). In addition, the involvement of VGLUT2 and VGLUT3 in, respectively, generalized and absence seizures has been proposed [23,25].…”

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Most, if not all of the approved antiepileptic drugs (AEDs) are not truly “antiepileptic” but merely “anti-seizures” (Van Liefferinge et al, 2013). Indeed, the AEDs do not stop epileptogenesis, the process of converting a normal brain to a brain with epilepsy, but at the most they reach complete seizure control.…”