Hyperekplexia, an inherited neuronal disorder characterized by exaggerated startle responses with unexpected sensory stimuli, is caused by dysfunction of glycinergic inhibitory transmission. From analysis of newly identified human hyperekplexia mutations in the glycine receptor (GlyR) α1 subunit, we found that an alanine-to-proline missense mutation (A384P) resulted in substantially higher desensitization level and lower agonist sensitivity of homomeric α1 GlyRs when expressed in HEK cells. The incorporation of the β subunit fully reversed the reduction in agonist sensitivity and partially reversed the desensitization of α1 The heteromeric α1β GlyRs showed enhanced desensitization but unchanged agonist-induced maximum responses, surface expression, main channel conductance, and voltage dependence compared with that of the wild-type α1β (α1β) GlyRs. Coexpression of the R392H and A384P mutant α1 subunits, which mimic the expression of the compound heterozygous mutation in a hyperekplexia patient, resulted in channel properties similar to those with α1 subunit expression alone. In comparison, another human hyperekplexia mutation α1, which was previously reported to enhance desensitization, caused a strong reduction in maximum currents in addition to the altered desensitization. These results were further confirmed by overexpression of α1 or α1 subunits in cultured neurons isolated from SD rats of either sex. Moreover, the IPSC-like responses of cells expressing α1β induced by repeated glycine pulses showed a stronger frequency-dependent reduction than those expressing α1β. Together, our findings demonstrate that A384 is associated with the desensitization site of the α1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia. Human startle disease is caused by impaired synaptic inhibition in the brainstem and spinal cord, which is due to either direct loss of GlyR channel function or reduced number of synaptic GlyRs. Considering that fast decay kinetics of GlyR-mediated inhibitory synaptic responses, the question was raised whether altered desensitization of GlyRs will cause dysfunction of glycine transmission and disease phenotypes. Here, we found that the α1 subunit mutation A384P, identified from startle disease patients, results in enhanced desensitization and leads to rapidly decreasing responses in the mutant GlyRs when they are activated repeatedly by the synaptic-like simulation. These observations suggest that the enhanced desensitization of postsynaptic GlyRs could be the primary pathogenic mechanism of human startle disease.

Amorphous indium-gallium-zinc-oxide thin-film transistors (a-IGZO-TFTs) with the LaAlO 3 /ZrO 2 gate dielectric stack employing a novel atmospheric pressure plasma jet process that results in small subthreshold swing and low threshold voltage are proposed and fabricated. The influence of post-deposition annealing (PDA) temperature on LaAlO 3 / ZrO 2 gate dielectric stack and device performance was investigated. The equivalent oxide thickness of the LaAlO 3 /ZrO 2 dielectric stack decreases from 11.5 nm without annealing to 7 nm after a 500°C annealing was applied. The LaAlO 3 /ZrO 2 /a-InGaZnO TFT with a 500°C annealing exhibits a small subthreshold swing of 77 mV•dec −1 , a high field-effect mobility of 9 cm 2 •V −1 •s −1 and an excellent current ratio of 1.8 × 10 7 , which could be attributed to the improved gate dielectric quality by the PDA. The LaAlO 3 /ZrO 2 /a-InGaZnO TFTs with excellent gate control ability allow the device to operate at a low operating voltage with low power consumption.

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