We review advances in understanding Purkinje cell (PC) complex spike (CS) physiology that suggest increased CS synchrony underlies syndromic essential tremor (ET). We searched PubMed for papers describing factors that affect CS synchrony or cerebellar circuits potentially related to tremor. Inferior olivary (IO) neurons are electrically coupled, with the degree of coupling controlled by excitatory and GABAergic inputs. Clusters of coupled IO neurons synchronize CSs within parasagittal bands via climbing fibers (Cfs). When motor cortex is stimulated in rats at varying frequencies, whisker movement occurs at ~10 Hz, correlated with synchronous CSs, indicating that the IO/CS oscillatory rhythm gates movement frequency. Intra-IO injection of the GABAA receptor antagonist picrotoxin increases CS synchrony, increases whisker movement amplitude, and induces tremor. Harmaline and 5-HT2a receptor activation also increase IO coupling and CS synchrony and induce tremor. The hotfoot17 mouse displays features found in ET brains, including cerebellar GluRδ2 deficiency and abnormal PC Cf innervation, with IO- and PC-dependent cerebellar oscillations and tremor likely due to enhanced CS synchrony. Heightened coupling within the IO oscillator leads, through its dynamic control of CS synchrony, to increased movement amplitude and, when sufficiently intense, action tremor. Increased CS synchrony secondary to aberrant Cf innervation of multiple PCs likely also underlies hotfoot17 tremor. Deep cerebellar nucleus (DCN) hypersynchrony may occur secondary to increased CS synchrony but might also occur from PC axonal terminal sprouting during partial PC loss. Through these combined mechanisms, increased CS/DCN synchrony may plausibly underlie syndromic ET.

The brain has traditionally been considered to be a target site of peripheral steroid hormones. On the other hand, extensive studies over the past thirty years have demonstrated that the brain is a site of biosynthesis of several steroids. Such steroids synthesized de novo from cholesterol in the brain are called neurosteroids. To investigate the biosynthesis and biological actions of neurosteroids in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. In the mid 1990s, the Purkinje cell, an important cerebellar neuron, was discovered as a major cell producing neurosteroids in the brain of vertebrates. It was the first demonstration of de novo neuronal biosynthesis of neurosteroids in the brain. Subsequently, neuronal biosynthesis of neurosteroids and biological actions of neurosteroids have become clear by the follow-up studies using the Purkinje cell as an excellent cellular model. Progesterone and estradiol, which are known as sex steroid hormones, are actively synthesized de novo from cholesterol in the Purkinje cell during development, when cerebellar neuronal circuit formation occurs. Importantly, progesterone and estradiol synthesized in the Purkinje cell promote dendritic growth, spinogenesis and synaptogenesis via their cognate nuclear receptors in the Purkinje cell. Neurotrophic factors may mediate these neurosteroid actions. Futhermore, allopregnanolone (3α,5α-tetrahydroprogesterone), a progesterone metabolite, is also synthesized in the cerebellum and acts on the survival of Purkinje cells. On the other hand, at the beginning of 2010s, the pineal gland, an endocrine organ located close to the cerebellum, was discovered as an important site of the biosynthesis of neurosteroids. Allopregnanolone, a major pineal neurosteroid, acts on the Purkinje cell for the survival of Purkinje cells by suppressing the expression of caspase-3, a crucial mediator of apoptosis. I as a recipient of Kobayashi Award from the Japan Society for Comparative Endocrinology in 2016 summarize the discovery of cerebellar and pineal neurosteroids and their biological actions on the growth and survival of Purkinje cells during development.

The inhibitory tone that the cerebellum exerts on the primary motor cortex (M1) is known as cerebellar brain inhibition (CBI). Studies show CBI to be relevant to several motor functions, including adaptive motor learning and muscle control. CBI can be assessed noninvasively via transcranial magnetic stimulation (TMS) using a double-coil protocol. Variability in parameter choice and controversy surrounding the protocol\'s ability to isolate the cerebellothalamocortical pathway casts doubt over its validity in neuroscience research. This justifies a systematic review of both the protocol, and its application. The following review examines studies using the double-coil protocol to assess CBI in healthy adults. Parameters and CBI in relation to task-based studies, other non-invasive protocols, over different muscles, and in clinical samples are reviewed. Of the 1398 studies identified, 24 met selection criteria. It was found that methodological design and selection of parameters in several studies may have reduced the validity of outcomes. Further systematic testing of CBI protocols is warranted, both from a parameter and task-based perspective.

We describe a 65-year-old woman with subacute cerebellar syndrome expressed as severe ataxia, and the presence of anti Purkinje cell antibodies (Anti-Yo). A small adnexal mass was only evident on PET CT with the pathological feature of fallopian tube adenocarcinoma. Anti-Yo antibodies have been strongly associated with paraneoplastic cerebellar degeneration, and nearly always associated to ovarian adenocarcinomas. Few cases have been reported in which this paraneoplastic syndrome has been related to fallopian tube adenocarcinoma. In this report, we discuss this association and its relation with fallopian tube and ovarian carcinoma.

Recombinant-methionyl human glial cell line-derived neurotrophic factor (GDNF) is known for its neurorestorative and neuroprotective effects in rodent and primate models of Parkinson\'s disease (PD). When administered locally into the putamen of Parkinsonian subjects, early clinical studies showed its potential promise as a disease-modifying agent. However, the development of GDNF for the treatment of PD has been significantly clouded by findings of cerebellar toxicity after continuous intraputamenal high-dose administration in a 6-month treatment/3-month recovery toxicology study in rhesus monkeys. Specifically, multifocal cerebellar Purkinje cell loss affecting 1-21% of the cerebellar cortex was observed in 4 of 15 (26.7%; 95% confidence interval [CI]: 10.5-52.4%) animals treated at the highest dose level tested (3000μg/month). No cerebellar toxicity was observed at lower doses (450 and 900μg/month) in the same study, or at similar or higher doses (up to 10,000μg/month) in subchronic or chronic toxicology studies testing intermittent intracerebroventricular administration. While seemingly associated with the use of GDNF, the pathogenesis of the cerebellar lesions has not been fully understood to date. This review integrates available information to evaluate potential pathogenic mechanisms and provide a consolidated assessment of the findings. While other explanations are considered, the existing evidence is most consistent with the hypothesis that leakage of GDNF into cerebrospinal fluid during chronic infusions into the putamen down-regulates GDNF receptors on Purkinje cells, and that subsequent acute withdrawal of GDNF generates the observed lesions. The implications of these findings for clinical studies with GDNF are discussed.