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Cerebellar climbing fibers convey sensorimotor information and their errors, which are used for motor control and learning. Furthermore, they represent reward-related information. Despite such functional diversity of climbing fiber signals, it is still unclear whether each climbing fiber conveys the information of single or multiple modalities and how the climbing fibers conveying different information are distributed over the cerebellar cortex. Here we perform two-photon calcium imaging from cerebellar Purkinje cells in mice engaged in a voluntary forelimb lever-pull task and demonstrate that climbing fiber responses in 68% of Purkinje cells can be explained by the combination of multiple behavioral variables such as lever movement, licking, and reward delivery. Neighboring Purkinje cells exhibit similar climbing fiber response properties, form functional clusters, and share noise fluctuations of responses. Taken together, individual climbing fibers convey behavioral information on multiplex variables and are spatially organized into the functional modules of the cerebellar cortex. Complex spike responses of a single mouse cerebellar Purkinje cell are modulated by multiple behavioral parameters in a self-initiated lever pull task, and there may be spatial modules of these cells to mediate functions of the cerebellar cortex. [ABSTRACT FROM AUTHOR]

[Display omitted] • Grin1 deletion in prospective parvalbumin interneurons reduces unitary GABA release. • Grin1 deletion in parvalbumin neurons impairs membrane properties and excitability. • No effect of Cav2.1 channel agonist on GABA release from Grin1 -deleted neurons. • Cav2.1-haploinsufficient parvalbumin neurons produce a similar GABA release deficit. • Grin1 deletion using parvalbumin promoter causes generally normal GABA release. N -methyl-D-aspartate receptor (NMDAR) hypofunction during brain development is likely to contribute to the manifestation of schizophrenia (SCZ) in young adulthood. The cellular targets of NMDAR hypofunction appear to be at least in part corticolimbic fast-spiking (FS) interneurons. However, functional alterations in parvalbumin (PV)-positive FS interneurons following NMDAR hypofunction are poorly understood. Paired patch-clamp recordings from murine cortical PV interneurons and pyramidal neurons revealed that genetic deletion of NMDAR subunit Grin1 in prospective PV interneurons before the second postnatal week impaired evoked- and synchronized-GABA release. Whereas intrinsic excitability and spiking characteristics were also disturbed by Grin1 deletion, neither restoring their excitability by K+ channel blockade nor increasing extracellular Ca2+ rescued the GABA release. GABA release was also insensitive to the Cav2.1 channel antagonist ω-agatoxin IVA. Heterozygous deletion of Cacna1a gene (encoding Cav2.1) in PV interneurons produced a similar GABA release phenotype as the Grin1 mutants. Treatment with the Cav2.1/2.2 channel agonist GV-58 augmented somatic Ca2+ currents and GABA release in Cacna1a -haploinsufficient PV interneurons, but failed to enhance GABA release in the Grin1 -deleted PV interneurons. Taken together, our results suggest that Grin1 deletion in prospective PV interneurons impairs proper maturation of membrane excitability and Cav2.1-recruited evoked GABA release. This may increase synaptic excitatory/inhibitory ratio in principal neurons, contributing to the emergence of SCZ-like phenotypes. [ABSTRACT FROM AUTHOR]

Group I metabotropic glutamate receptors (mGluRs) include mGluR1 and mGluR5, which are coupled to the Gq family of heterotrimeric G-proteins and readily activated by their selective agonist 3,5-dihydroxyphenilglycine (DHPG). mGluR1 and mGluR5 exhibit nearly complementary distributions spatially or temporally in the central nervous system (CNS). In adult cerebellar Purkinje cells (PCs), mGluR1 is a dominant group I mGluR and mGluR5 is undetectable. mGluR1 expression increases substantially during the first three weeks of postnatal development and remains high throughout adulthood. On the other hand, mGluR5 expression is observed during the first two postnatal weeks and then decreases. However, functional differences between mGluR1 and mGluR5 in the CNS remains to be elucidated. To address this issue, we generated "mGluR5-rescue" mice in which mGluR5 is specifically expressed in PCs in global mGluR1-knockout (KO) mice. mGluR5-rescue mice exhibited apparently normal motor coordination, developmental elimination of redundant climbing fiber (CF)-PC synapses, and delay eyeblink conditioning, which were severely impaired in mGluR1-KO mice. We concluded that mGluR5 is functionally comparable with mGluR1 in cerebellar PCs. [ABSTRACT FROM AUTHOR]

The cerebellum is essential for the control, coordination, and learning of movements, and for certain aspects of cognitive function. Purkinje cells are the sole output neurons in the cerebellar cortex and therefore play crucial roles in the diverse functions of the cerebellum. The type 1 metabotropic glutamate receptor (mGluR1) is prominently enriched in Purkinje cells and triggers downstream signaling pathways that are required for functional and structural plasticity, and for synaptic responses. To understand how mGluR1 contributes to cerebellar functions, it is important to consider not only the operational properties of this receptor, but also its spatial organization and the molecular interactions that enable its proper functioning. In this review, we highlight how mGluR1 and its related signaling molecules are organized into tightly coupled microdomains to fulfill physiological functions. We also describe emerging evidence that altered mGluR1 signaling in Purkinje cells underlies cerebellar dysfunction in ataxias of human patients and mouse models. • mGluR1 signaling in Purkinje cells is crucial for various cerebellar functions. • mGluR1 triggers intracellular pathways for neural plasticity and modulation. • mGluR1 and its interacting partners are arranged into tightly coupled microdomains. • mGluR1 signaling is a promising therapeutic target for cerebellar dysfunctions. [ABSTRACT FROM AUTHOR]

Carbon fiber and carbon fiber disc microelectrodes are widely used for electrochemical detection of biochemicals released from cells. However, fabricating these types of microelectrodes is difficult and time-consuming. Here, we report an easy-to-fabricate, carbon powder-filled microelectrode consisting of a pulled glass capillary backfilled with carbon powder. Carbon tip size and responsiveness can be controlled by adjusting the settings of the puller. Carbon powder-filled microelectrodes with tip opening diameters of 7–24 μm detected sub-micromolar to sub-millimolar levels of dopamine and catecholamines released from PC-12 cells. This simple microelectrode should promote further work on cellular and tissue electrochemistry. [Display omitted] • Carbon fiber microelectrodes are standard tools for cellular electrochemistry. • However, fabrication of such a microelectrode is difficult and time-consuming. • We devised an easy-to-fabricate carbon powder-filled microelectrode. • This electrode could be used for detecting biochemical release from a living cell. [ABSTRACT FROM AUTHOR]