BACKGROUND: Anti-Purkinje cell cytoplasmic antibody type 2 (PCA-2) is associated with various neurological conditions in adults. However, related studies have not been conducted in children. The present study aimed to characterize the clinical features and outcomes of PCA-2-related autoimmune cerebellar degeneration in pediatric patients.
METHODS: A total of 357 pediatric patients with acute or subacute cerebellar ataxia were recruited for the study from June 2015 to September 2022. Of these, PCA-2 was identified in four patients. Information on the clinical manifestations, patient response to treatment, and outcomes was collected and analyzed.
RESULTS: The patient cohort in the present study included two boys and two girls, with the age of onset from six to 12 years. Axial ataxia was the most remarkable symptom observed in the entire patient cohort (four of four), followed by dysmetria in 75% (three of four), dysarthria in 50% (two of four), and nystagmus in 25% (one of four) of patients. Cognitive impairment was present in one patient. Peripheral neuropathy, which is an extracerebellar symptom, was found in two patients. One patient was diagnosed with a pelvic neuroblastoma before the onset of ataxia. The presence of oligoclonal bands was confirmed in the cerebrospinal fluid, and cerebellar atrophy was observed. Immunotherapy, including glucocorticoids and/or intravenous immunoglobulin, was administered to all four patients immediately following diagnosis, and mycophenolate mofetil was administered to three patients. Three patients responded to immunotherapy.
CONCLUSIONS: In children, PCA2-associated autoimmune cerebellar degeneration is rare, and they show comparatively fewer symptoms than adults. Timely and appropriate immunotherapy is beneficial.

Spliceosomal GTPase elongation factor Tu GTP binding domain containing 2 (EFTUD2) is a causative gene for mandibulofacial dysostosis with microcephaly (MFDM) syndrome comprising cerebellar hypoplasia and motor dysfunction. How EFTUD2 deficiency contributes to these symptoms remains elusive. Here, we demonstrate that specific ablation of Eftud2 in cerebellar Purkinje cells (PCs) in mice results in severe ferroptosis, PC degeneration, dyskinesia, and cerebellar atrophy, which recapitulates phenotypes observed in patients with MFDM. Mechanistically, Eftud2 promotes Scd1 and Gch1 expression, upregulates monounsaturated fatty acid phospholipids, and enhances antioxidant activity, thereby suppressing PC ferroptosis. Importantly, we identified transcription factor Atf4 as a downstream target to regulate anti-ferroptosis effects in PCs in a p53-independent manner. Inhibiting ferroptosis efficiently rescued cerebellar deficits in Eftud2 cKO mice. Our data reveal an important role of Eftud2 in maintaining PC survival, showing that pharmacologically or genetically inhibiting ferroptosis may be a promising therapeutic strategy for EFTUD2 deficiency-induced disorders.

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), learning difficulties, and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors are also prominent in Astn2 cKO animals, but they do not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrate a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

Toll-like receptor (TLR) 4 contributes to be the induction of neuroinflammation by recognizing pathology-associated ligands and activating microglia. In addition, numerous physiological signaling factors act as agonists or antagonists of TLR4 expressed by non-immune cells. Recently, TLR4 was found to be highly expressed in cerebellar Purkinje neurons (PNs) and involved in the maintenance of motor coordination through non-immune pathways, but the precise mechanisms remain unclear. Here we report that mice with PN specific TLR4 deletion (TLR4PKO mice) exhibited motor impairments consistent with cerebellar ataxia, reduced PN dendritic arborization and spine density, fewer parallel fiber (PF) - PN and climbing fiber (CF) - PN synapses, reduced BK channel expression, and impaired BK-mediated after-hyperpolarization, collectively leading to abnormal PN firing. Moreover, the impaired PN firing in TLR4PKO mice could be rescued with BK channel opener. The PNs of TLR4PKO mice also exhibited abnormal mitochondrial structure, disrupted mitochondrial endoplasmic reticulum tethering, and reduced cytosolic calcium, changes that may underly abnormal PN firing and ultimately drive ataxia. These results identify a previously unknown role for TLR4 in regulating PN firing and maintaining cerebellar function.

BACKGROUND: Preterm newborns struggle with maintaining an adequate respiratory pattern; early caffeine administration is suggested to stimulate respiration and reduce bronchopulmonary dysplasia, however, its consequences on the immature cerebellum remains unknown. This study aimed to assess the impact of early caffeine administration, at standard and high doses, accompanied by supplemental oxygen on cerebellar development in an experimental model.
METHODS: Five groups of Wistar pups were formed (n = 8 offspring/group): (a) negative control: no intervention; (b) placebo: pups remaining from birth until the 7th day of life (DOL) exposed to fractional inspired oxygen (FiO2) 45%, resembling preterm infant condition and as a placebo, 0.2 mL oral 5% dextrose, from the first DOL until the 14th DOL; (c) caffeine group: oral caffeine, 1st DOL 20 mg/kg, and from 2nd to 14th DOL, 5 mg/kg (standard dose); (d) caffeine at the standard dose, plus O2: during the first 7 DOLs (FiO2: 45%); (e) caffeine: 40 mg/kg in the first DOL, 10 mg/kg the next 14 DOLs, plus O2 in the first 7 DOLs (FiO2: 45%). Subjects were sacrificed on their 15th DOL; measurements were taken from the cerebellum, specifically the external granular layer (EGL) and molecular layer (ML), with quantification of cell migration.
RESULTS: Caffeine administration in pups resulted in a delay in cerebellum development based on persistent transitional EGL cells; this finding was exacerbated in groups exposed to caffeine plus O2, as evident from the thicker EGL. The negative control group showed near-complete cell migration with a thicker ML and a significantly smaller EGL.
CONCLUSIONS: Early caffeine administration in newborn rats disrupts cerebellar cortex cell processes and connectivity pathways, with exacerbated effects in groups receiving caffeine plus O2.

This review article will cover the recent developments in the new evolving field of Purkinje bioengineering and the development of human Purkinje networks. Recent work has progressed to the point of a methodological and systematic process to bioengineer Purkinje networks. This involves the development of 3D models based on human anatomy, followed by the development of tunable biomaterials, and strategies to reprogram stem cells to Purkinje cells. Subsequently, the reprogrammed cells and the biomaterials are coupled to bioengineer Purkinje networks, which are then tested using a small animal injury model. In this article, we discuss this process as a whole and then each step separately. We then describe potential applications of bioengineered Purkinje networks and challenges in the field that need to be overcome to move this field forward. Although the field of Purkinje bioengineering is new and in a state of infancy, it holds tremendous potential, both for therapeutic applications and to develop tools that can be used for disease modeling.

Placebo effects are notable demonstrations of mind-body interactions1,2. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain-a phenomenon known as placebo analgesia3-6. However, despite the strength of placebo effects and their impact on everyday human experience and the failure of clinical trials for new therapeutics7, the neural circuit basis of placebo effects has remained unclear. Here we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn)-a precerebellar nucleus with no established function in pain. We created a behavioural assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain-relief expectation, providing cellular-level evidence for a role of the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain.

Behavioral and pharmaceutical interventions reverse defects associated with increased cerebellar long-term depression in a mouse model of Fragile X syndrome.

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The cerebellum, a phylogenetically ancient brain region, has long been considered strictly a motor control structure. Recent studies have implicated the cerebellum in cognition, sensation, emotion and autonomic function, making it an important target for further investigation. Here, we show that cerebellar Purkinje neurons in mice are activated by the hormone asprosin, leading to enhanced thirst, and that optogenetic or chemogenetic activation of Purkinje neurons induces rapid manifestation of water drinking. Purkinje neuron-specific asprosin receptor (Ptprd) deletion results in reduced water intake without affecting food intake and abolishes asprosin\'s dipsogenic effect. Purkinje neuron-mediated motor learning and coordination were unaffected by these manipulations, indicating independent control of two divergent functions by Purkinje neurons. Our results show that the cerebellum is a thirst-modulating brain area and that asprosin-Ptprd signaling may be a potential therapeutic target for the management of thirst disorders.