Atlastin‐1 modulates seizure activity and neuronal excitability

Abstract

Epilepsy is a neurological disease, and the main clinical manifestation is recurrent seizures. The exact etiology of epilepsy and the pathogenesis of the disorder are not yet fully understood. Atlastin‐1, a dynamin‐like GTPase, interacts with microtubules and is responsible for vesicle formation, both of which are highly associated with the development of epilepsy. Here, we reported that the expression level of atlastin‐1 protein was reduced in the temporal neocortex of patients with temporal lobe epilepsy and in the hippocampus and adjacent cortex of a pentylenetetrazol‐kindled epileptic mouse model. Cells expressing atlastin‐1 coexpressed the inhibitory synaptic marker GAD67 in the temporal cortex and hippocampus of patients with epilepsy and an epileptic mouse model. The lentivirus‐mediated overexpression of atlastin‐1 protein in the hippocampus of mice suppressed seizure activity in behavioral experiments. Patch‐clamp recordings in the Mg2+‐free epilepsy cell model showed that atlastin‐1 overexpression inhibited neuronal excitability by suppressing the discharge frequency of spontaneous action potentials rather than by changing the passive and active properties of action potentials. Inhibitory synaptic transmission, but not excitatory synaptic currents, increased after atlastin‐1 overexpression. These findings suggest that atlastin‐1 likely contributes to the occurrence and development of epilepsy through inhibitory synaptic transmission.

Dynamic Transitions in Neuronal Network Firing Sustained by Abnormal Astrocyte Feedback

“…The seizure-like firing is more severe and synchronized; eventually, the firing of the pyramidal neuronal population changes from asynchronous firing ( Figure 3 (e)) to seizure-like synchronous firing ( Figure 3(f) ). The yellow strip area in Figure 3(f) indicates that the neuronal population is in a state of seizure-like synchronous firing and then resumes normal firing later, and experiments have shown that epilepsy firing reflects the synchronous firing of the neuronal population [ 4 , 58 ].…”

“…Epilepsy is one of the most common neurological diseases, affecting nearly 70 million people worldwide, and it is characterized by the aberrant synchronous firing of neurons [ 1 – 3 ]. It is generally believed that the reason for the aberrant synchronous firing of neurons is the imbalance between synaptic excitability and inhibition [ 4 – 6 ], which is caused by changes in the structure and function of neurons themselves, including changes in neurotransmitters and mutations in receptors, ion channels, and ion transporters, and alterations in network topology [ 7 ]. However, decades of studies have found that the abnormal feedback effect of astrocytes on neurons has a critical effect on the balance of neuronal excitability and inhibition and can even cause epilepsy [ 8 – 10 ].…”

A novel insertion mutation in atlastin 1 is associated with spastic quadriplegia, increased membrane tethering, and aberrant conformational switching

“…As is the case in some complex HSP cases, the proband here has shown features of epilepsy as established by an EEG. Recently, significantly decreased ATL1 expression levels have been identified in the temporal lobe neocortex of patients with temporal lobe epilepsy (TLE) ( 66 ). Upon overexpression of ATL1 in an epileptic mouse model, seizure occurrence decreased resulting from inhibition of spontaneous action potential.…”

ER Morphology in the Pathogenesis of Hereditary Spastic Paraplegia

“…ATL2 GTPase activity has been reported to contribute to IP3-induced dendritic Ca 2+ signals in primary hippocampal neurons [ 57 ] and depletion of ATLs affects store-operated Ca 2+ entry in PC-12 cells [ 58 ], hinting that atlastins may influence Ca 2+ homeostasis. This notion may be supported by a report that Atlastin-1 modulates seizure activity and neuronal excitability [ 59 ] and the observation that Drosophila atlastin decreases evoked transmitter release at the neuromuscular junction and causes age-dependent decline in adult locomotion [ 57 , 60 ], even though both works surmise that interference with BMP trafficking could also be a potential source of these phenotypes, conceivably suggesting that perturbation of trafficking could underlie HSP-disease. Indeed, HSP-causing mutations were shown to disrupt BMP receptors II trafficking to the cell surface in HEK239-T cells [ 61 ] and knockdown of zebrafish atl1 decreases larval mobility, perturbs the architecture of spinal motor axons and is associated with a substantial upregulation of the BMP signaling pathway, again implying that atlastins may regulate BMP receptor trafficking [ 62 ].…”