Ca2+ signals are highly regulated in a spatiotemporal manner in numerous cellular physiological events. Here we report a genetically engineered blue light-activated Ca2+ channel switch (BACCS), as an optogenetic tool for generating Ca2+ signals. BACCS opens Ca2+-selective ORAI ion channels in response to light. A BACCS variant, dmBACCS2, combined with Drosophila Orai, elevates the Ca2+ concentration more rapidly, such that Ca2+ elevation in mammalian cells is observed within 1 s on light exposure. Using BACCSs, we successfully control cellular events including NFAT-mediated gene expression. In the mouse olfactory system, BACCS mediates light-dependent electrophysiological responses. Furthermore, we generate BACCS mutants, which exhibit fast and slow recovery of intracellular Ca2+. Thus, BACCSs are a useful optogenetic tool for generating temporally various intracellular Ca2+ signals with a large dynamic range, and will be applicable to both in vitro and in vivo studies.

Phosphatidylinositol-3,4,5-trisphosphate (PIP3) is highly regulated in a spatiotemporal manner and plays multiple roles in individual cells. However, the local dynamics and primary functions of PIP3 in developing neurons remain unclear because of a lack of techniques for manipulating PIP3 spatiotemporally. We addressed this issue by combining optogenetic control and observation of endogenous PIP3 signaling. Endogenous PIP3 was abundant in actin-rich structures such as growth cones and “waves”, and PIP3-rich plasma membranes moved actively within growth cones. To study the role of PIP3 in developing neurons, we developed a PI3K photoswitch that can induce production of PIP3 at specific locations upon blue light exposure. We succeeded in producing PIP3 locally in mouse hippocampal neurons. Local PIP3 elevation at neurite tips did not induce neurite elongation, but it was sufficient to induce the formation of filopodia and lamellipodia. Interestingly, ectopic PIP3 elevation alone activated membranes to form actin-based structures whose behavior was similar to that of growth-cone-like “waves”. We also found that endocytosis regulates effective PIP3 concentration at plasma membranes. These results revealed the local dynamics and primary functions of PIP3, providing fundamental information about PIP3 signaling in neurons.

The clinical characteristics of Guillain-Barré syndrome (GBS) after coronavirus disease 2019 (COVID-19) remain unclear due to the small number of cases. We herein report a case of a Japanese patient with post-COVID-19 GBS who presented with facial and limb muscle weakness, sensory deficits, and autonomic dysfunction. Nerve conduction studies revealed demyelination. Head magnetic resonance imaging showed contrast enhancement in the bilateral facial nerves. Systemic management, including intubation, intravenous immunoglobulin therapy, and rehabilitation, improved the patient's condition. This was the first Japanese case of acute inflammatory demyelinating polyneuropathy after COVID-19 and was characterized by autonomic dysfunction and facial nerve enhancement.

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome has previously been reported in only 2 patients with progressive supranuclear palsy (PSP). Herein, we report a third case of WEBINO syndrome with PSP. The patient was an 81-year-old man who had experienced gradually increasing gait disturbance and occasional falls since the age of 78 years. At 80 years of age, he presented with cognitive impairment, parkinsonism, and oculomotor abnormalities. The oculomotor abnormalities consisted of vertical gaze palsy and loss of eye convergence. Brain magnetic resonance imaging demonstrated marked atrophy of the midbrain. He was diagnosed with PSP. At the age of 81 years, he presented with alternating extropia in his forward gaze and adduction paresis and outward nystagmus of the abducted eye in his horizontal gaze, both of which were compatible with WEBINO syndrome. Previously, we reported the first case of PSP with WEBINO syndrome, and another group recently reported a second case. In light of the previous cases and the present case, WEBINO syndrome in PSP should not be considered extremely rare. Furthermore, WEBINO syndrome has not been reported in other neurodegenerative disorders, which suggests that it might be a useful and specific diagnostic finding in PSP.

BackgroundNivolumab is an immune checkpoint inhibitor (ICI) and is used for the treatment of advanced non-small cell lung cancer (NSCLC). Several immune-mediated neurological adverse events associated with ICIs have been reported to date, such as Guillain-Barré syndrome. Nivolumab-associated neurological adverse events can vary, and their etiology remains unclear.Case presentationA 72-year-old man with NSCLC was treated with nivolumab as a second-line therapy. After 13 rounds of nivolumab therapy, he presented with Ramsay-Hunt syndrome (RHS) followed by acute ataxic sensory neuropathy. Antiviral therapy for Varicella-Zoster virus and prednisolone resulted in partial improvement of RHS, while almost no recovery was observed in the sensory neuropathy. However, the sensory ataxia significantly improved after intravenous immunoglobulin (IVIg) therapy, and interestingly, the facial palsy associated with RHS also improved. The neurological manifestations, nerve conduction study result, and imaging findings supported that dorsal root ganglia were the primary lesion site of acute ataxic sensory neuropathy.ConclusionsOur case presented with the comorbidity of RHS and subsequent ataxic sensory neuropathy after nivolumab therapy to whom IVIg was effective. Our case suggested the wide variability of possible neurological symptoms, and the potential usefulness of IVIg to sensory ataxic neuropathy, seen in cancer patients with ICI treatment.