Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (K(Ca)) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that K(Ca) channels may constitute a potential therapeutic target in EA2.

The study of the gut microbiome has increasingly revealed an important role in modulating brain function and mental health. In this review, we underscore specific pathways and mechanisms by which the gut microbiome can promote the development of mental disorders such as depression and anxiety. First, we review the involvement of the stress response and immune system activation in the development of depression and anxiety. Then, we examine germ‐free murine models used to uncover the role of the gut microbiome in developing and modulating pertinent activity in the brain and the immune system. We also document multiple pathways by which stress‐induced inflammation harms brain function and ultimately affects mental health, and review how probiotic and prebiotic treatments have shown to be beneficial. Lastly, we provide an overview of gut microbiome‐derived compounds (short‐chain fatty acids, tryptophan catabolites, microbial pattern recognition) and related mechanisms (vagal nerve activity and fecal microbiota transplants) involved in mediating the influence of the gut microbiome to mental health. Overall, a picture of the gut microbiome playing a facilitating role between stress response, inflammation, and depression, and anxiety is emerging. Future research is needed to firmly establish the microbiome's causal role, to further elucidate the mechanisms by which gut microbes influence brain function and mental health, and to possibly develop treatments that improve mental health through microbiotic targets.

Mormyrid electric fish are a model system for understanding how neural circuits predict the sensory consequences of motor acts. Medium ganglion cells in the electrosensory lobe create negative images that predict sensory input due to the fish’s electric organ discharge (EOD). Previous studies showed that negative images could be created through plasticity at granule cell-medium ganglion cell synapses provided that granule cell responses to the brief EOD command were sufficiently varied and prolonged. Here we show for the first time that granule cells indeed provide such a temporal basis, and that it is well matched to the temporal structure of self-generated sensory inputs, allowing for rapid and accurate sensory cancellation and explaining paradoxical features of negative images. We also demonstrate an unexpected and critical role for unipolar brush cells (UBCs) in generating the required delayed responses. These results provide a mechanistic account of how copies of motor commands are transformed into sensory predictions.

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A key component of recent theories on cerebellar function is rebound firing in neurons of the deep cerebellar nuclei (DCN). Despite the robustness of this phenomenon in vitro, in vivo studies have provided little evidence for its prevalence. Here we show that under physiological conditions, in vitro or in vivo, mice or rat DCN neurons rarely show rebound firing, a finding that necessitates a critical re-evaluation of recent cerebellar models.A vast amount of cortical and sensory information that converges onto the cerebellum is integrated by cerebellar Purkinje cells and subsequently conveyed to the neurons of the deep cerebellar nuclei (DCN) 1 . DCN neurons further process this information and generate the major output of the cerebellum, encoding the computational outcome of the cerebellar circuitry in their rate and temporal pattern of activity.A stereotypic biophysical feature of DCN neurons is that they are capable of rebound depolarization 2-4 . Following a strong hyperpolarization their membrane potential briefly rebounds to a more depolarized level resulting in a transient increase in their firing rate; a phenomenon termed rebound firing 4,5 . Given the inhibitory GABAergic nature of Purkinje cell synapses onto DCN neurons, and primarily on the basis of this stereotypic biophysical property in vitro, rebound firing has been extensively incorporated into recent theories of cerebellar function 6-8 . Several functional roles, from timing to encoding information and mediating plasticity have been assigned to rebound depolarization and firing 6-10 . However, even though rebound firing is robust when examined using intracellular recordings in vitro, there is little direct evidence in support of its physiological prevalence in vivo 11-13 . We investigated this discrepancy. DCN rebound depolarization is most likely mediated by low-threshold T-type calcium channels 3-5 . Factors that determine the extent of rebound are average membrane potential prior to hyperpolarization, and the level and duration of hyperpolarization 2,4,5 . Using acutely prepared rat cerebellar slices, we designed our experiments to replicate these factors as close to their physiological parameters as possible (see Supplemental data). We avoided intracellular recordings because they inevitably alter the membrane input resistance, and the cytosolic ionic composition. Therefore, we monitored the activity of DCN neurons extracellularly to preserve their baseline firing rate and the true reversal potential of their GABAergic inputs. Two sets of experiments were done to mimic strong hyperpolarizations that may occur under NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript physiological conditions. First, with excitatory transmission blocked, GABAergic synaptic inputs were stimulated using a train of 10 electrical pulses at 100 Hz (Fig. 1a). The strength of the stimulation was adjusted such that it efficiently paused firing in the target cell (average pause duration = 199.3 ± 9.1 ms, n = 39 cells). Using this paradigm...