sIPSCs are spontaneous inhibitory post synaptic currents. Deactivation τ is similar to that of activation, referring instead to the time constant of population closing. Activation V½ is the potential at which the population of channels is half maximally activated which the accompanying τ is the time constant of the populations activation. , ,, ,, ,, Ĭurrent amplitude refers to the amount of current through mutant versus wild-type channels in cell culture or oocyte assays. Shorter mean open time, more and larger sIPSCs in Mice Shorter mean open time and smaller single channel conductance Mutations in KCNA1 related to episodic ataxia type-1 As these channels are important in the regulation of Purkinje cell activity, it is likely that this results increased and aberrant inhibitory input into Purkinje cells and, thus, disrupted Purkinje cell firing and cerebellum output. It is assumed, though not yet proven, that decrease in K V1.1 mediated current leads to prolonged action potentials in interneurons and basket cells. While these biophysical changes in channel properties likely underlie some of the decrease in current observed in experiments, many mutations also seem to result in misfolded or otherwise mistrafficked channels, which is likely to be the major cause of dysfunction and disease pathogenesis. Some of these mutations, moreover, produce channels that deactivate at faster rates (deactivation τ), which would also result in decreased current through these channels. Furthermore, these channels tend to activate at more positive potentials and slower rates, demonstrated by positive shifts in their V½ values and slower τ activation time constants, respectively. As described in Table 1, most of the known EA1 associated mutations result in a drastic decrease in the amount of current through K V1.1 channels. 15 of these mutations have been at least partly characterized in cell culture based electrophysiological assays wherein 14 of these 15 mutations have demonstrated drastic alterations in channel function. There are currently 17 K V1.1 mutations associated with EA1, Table 1 and Figure 1. The channels aid in the repolarization phase of action potentials, thus affecting inhibitory input into Purkinje cells and, thereby, all motor output from the cerebellum.
K V1.1 is expressed heavily in basket cells and interneurons that form GABAergic synapses on Purkinje cells. Mutations of the gene KCNA1, which encodes the voltage-gated potassium channel K V1.1, are responsible for this subtype of episodic ataxia. Onset of EA1 occurs during early childhood to adolescence and persists throughout the patient's life. This disorder is also known as episodic ataxia with myokymia (EAM), hereditary paroxysmal ataxia with neuromyotonia and Isaacs-Mertens syndrome. Type 1 episodic ataxia (EA1) is characterized by attacks of generalized ataxia induced by emotion or stress, with myokymia both during and between attacks. Schematic structure of K V1.1 with the episodic ataxia type 1 mutations noted in red. Seizures are likely due to altered firing of hippocampal neurons (KCNA1 null mice have seizures for this reason). This is either due to direct malfunction of these cells, such as in EA2, or improper regulation of these cells, such as in EA1. Ataxia, the most common symptom, is due to misfiring of Purkinje cells in the cerebellum. The various symptoms of EA are caused by dysfunction of differing areas. Other patients have nystagmus, vertigo, tinnitus, diplopia or seizures. Some patients also have continuous tremors of various motor groups, known as myokymia.
Typically, episodic ataxia presents as bouts of ataxia induced by startle, stress, or exertion.
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