The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca V 3.1 T-type Ca 2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4-to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca V 3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca V 3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4-to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca V 3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca V 3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca V 3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.subthreshold oscillation | T-type calcium channel | harmaline

Primary intraocular lymphoma is a lymphoma that occurs in the eye, and is a subtype of primary central nervous system lymphoma that occurs in the brain, spinal cord, and meninges. It is composed of diffuse large B cell type. The pathophysiology and cause are not known exactly, and future research is needed. However, viral infection is thought to be the cause in immunocompromised patients. Diagnostic methods include fluorescein angiography, retinal tomography, and ocular magnetic resonance imaging. The main diagnostic method is cytopathology, but due to its false-negative rates the interleukin (IL)-10 cytokine, known as a growth factor for malignant B-lymphocytes in primary intraocular lymphoma, can be helpful in diagnosis. In the case of primary intraocular lymphoma, intravitreal methotrexate injection can be performed. Ratio of IL-10/IL-6 is greater than 1 before treatment and decreases to less than 1 after treatment. Although the prognosis is poor, it is expected to increase the survival rate through research on diagnostic methods and intraocular injection treatment combined with systemic chemotherapy and radiation therapy.