Excitation and Excitability of Unipolar Brush Cells

__Abstract__ The cerebellum is a distinct brain structure that ensures the spatial accuracy and temporal coordination of movements. It is located superimposed on the brainstem and has an appearance and organization unlike that of the cerebral cortex: its surface has a highly regular foliation pattern, and its neural circuitry is organized in repeated structured modules. Neural activity enters the cerebellum via two excitatory pathways, the mossy ber system and the climbing ber system. Climbing bers originate from the inferior olivary nucleus in the brainstem, and assert a powerful in uence on cerebellar output and long-term adaptation processes. Mossy bers originate from a large number of sources, and carry contextual information on sensory inputs, aspects of motor planning and commands, and proprioceptive feedback. In the cerebellum this information is evaluated and integrated, to produce neural output that in uences ongoing movement directly. Mossy ber signals are processed in the cerebellum in three stages. In the granular layer, the input stage of the cerebellum, mossy ber signals undergo a recoding step where they are combined and expanded by granule cells. Next, in the molecular layer, granule cell signals are integrated with climbing ber signals in Purkinje cells. Together, the granular la

Forward Signaling by Unipolar Brush Cells in the Mouse Cerebellum

Unipolar brush cells (UBCs) are glutamatergic interneurons prominently present in the granular layer of the vestibulocerebellum. UBCs engage in extensive synaptic contact with a single presynaptic mossy fiber and signal to downstream granule cells through an elaborate network of mossy fiber-like axons. Ultrastructural examinations and electrophysiological recordings in organotypic slice cultures have indicated that UBCs target not only granule cells but also other UBCs, thus forming chains of two or perhaps more interconnected UBCs. In this report, we show recordings of spontaneous and evoked (di)synaptic events in granule cells and UBCs in fresh cerebellar slices from juvenile mice (5–7 weeks). The patterns of arrival of synaptic events were consistent with the presence of a presynaptic UBC, and recordings from UBCs displayed spontaneous protracted synaptic events characteristic of UBC excitatory synaptic transmission. These results highlight that chains of UBCs could further extend the temporal range of delayed and protracted signaling in the cerebellar cortical network

An outbreak of Clostridium difficile infections due to new PCR ribotype 826

__Objectives:__ To investigate an unusual outbreak of five patients with a total of eight episodes of a Clostridium difficile infection on a gastrointestinal surgical ward of a Dutch tertiary-care, university-affiliated hospital. __Methods:__ Clinical case investigations and laboratory analyses were performed. Laboratory analyses included PCR ribotyping, multiple-locus variable-number tandem repeat analysis typing, toxin typing, antimicrobial susceptibility testing and whole genome sequencing. __Results:__ The outbreak was associated with recurrent and severe disease in two of five patients. All episodes were due to a unique ribotype that was not recognized in the collection of an international network of reference laboratories and was assigned PCR ribotype 826. PCR ribotype 826 is a toxin A-, toxin B- and binary toxin-positive ribotype which according to molecular typing belongs to clade 5 and resembles the so-called hypervirulent ribotype 078. The presence of a clonal outbreak was confirmed by whole genome sequencing, yet the source of this newly identified ribotype remained unclear. __Conclusions:__ This newly identified C. difficile PCR ribotype 826 is part of clade 5 and might also have increased virulence. The recognition of this outbreak highlights the need for ongoing C. difficile infection surveillance to monitor new circulating ribotypes with assumed increased virulence

Variable timing of synaptic transmission in cerebellar unipolar brush cells

The cerebellum ensures the smooth execution of movements, a task that requires accurate neural signaling on multiple time scales. Computational models of cerebellar timing mechanisms have suggested that temporal information in cerebellum-dependent behavioral tasks is in part computed locally in the cerebellar cortex. These models rely on the local generation of delayed signals spanning hundreds of milliseconds, yet the underlying neural mechanism remains elusive. Here we show that a granular layer interneuron, called the unipolar brush cell, is well suited to represent time intervals in a robust way in the cerebellar cortex. Unipolar brush cells exhibited delayed increases in excitatory synaptic input in response to presynaptic stimulation in mouse cerebellar slices. Depending on the frequency of stimulation, delays extended from zero up to hundreds of milliseconds. Such controllable protraction of delayed currents was the result of an unusual mode of synaptic integration, which was well described by a model of steady-state AMPA receptor activation. This functionality extends the capabilities of the cerebellum for adaptive control of behavior by facilitating appropriate output in a broad temporal window

Cerebellar ataxia by enhanced Cav2.1 currents is alleviated by Ca2+-dependent K-channel activators in Cacna1aS218l mutant mice

Mutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α1A-subunit of CaV2.1 channels and thereby either decrease or increase neuronal Ca2+ influx. A decreased CaV2.1-mediated Ca2+ influx has been shown to reduce the regularity of cerebellar Purkinje cell activity and to induce episodic cerebellar ataxia. However, little is known about how ataxia can be caused by CACNA1A mutations that increase the Ca2+ influx, such as the S218L missense mutation. Here, we demonstrate that the S218L mutation cause

Role of olivary electrical coupling in cerebellar motor learning

The level of electrotonic coupling in the inferior olive is extremely high, but its functional role in cerebellar motor control remains elusive. Here, we subjected mice that lack olivary coupling to paradigms that require learning-depend ent timing. Cx36-deficient mice showed impaired timing of both locomotion and eye-blink responses that were conditioned to a tone. The latencies of their olivary spike activities in response to the unconditioned stimulus were significantly more variable than those in wild-types. Whole-cell recordings of olivary neurons in vivo showed that these differences in spike timing result at least in part from altered interactions with their subthreshold oscillations. These results, combined with analyses of olivary activities in computer simulations at both the cellular and systems level, suggest that electrotonic coupling among olivary neurons by gap junctions is essential for proper timing of their action potentials and thereby for learning-dependent timing in cerebellar motor control