Neuroscience
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In the last 50 years, our vision of the cerebellum has vastly evolved starting with Voogd's (1967) description of extracerebellar projections' terminations and how the projection maps transformed the presumptive homogeneity of the cerebellar cortex into a more complex center subdivided into transverse and longitudinal distinct functional zones. The picture became still more complex with Richard Hawkes and colleagues' (Gravel et al., 1987) discovery of the biochemical heterogeneity of Purkinje cells (PCs), by screening their molecular identities with monoclonal antibodies. ⋯ The correlation of these two maps in adult cerebellum shows a perfect matching of developmental mechanisms. This review discusses a series of arguments in favor of the essential role played by PCs in organizing the microzonation of the cerebellum during development (the "matching" hypothesis).
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Masao Ito proposed a cerebellar learning hypothesis with Marr and Albus in the early 1970s. He suggested that cerebellar flocculus (FL) Purkinje cells (PCs), which directly inhibit the vestibular nuclear neurons driving extraocular muscle motor neurons, adaptively control the horizontal vestibulo-ocular reflex (HVOR) through the modification of mossy and parallel fiber-mediated vestibular responsiveness by visual climbing fiber (CF) inputs. Later, it was suggested that the same FL PCs adaptively control the horizontal optokinetic response (HOKR) in the same manner through the modification of optokinetic responsiveness in rodents and rabbits. ⋯ Today, their hypothesis is considered as a fundamental mechanism of cerebellar learning. Furthermore, it was found that the memory of adaptation is transferred from the FL to vestibular nuclei for consolidation by repetition of adaptation through the plasticity of vestibular nuclear neurons. In this article, after overviewing their cerebellar learning hypothesis, I discuss possible roles of LTD and LTP in gain-up and gain-down HVOR/HOKR adaptations and refer to the expansion of their hypothesis to cognitive functions.
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Molecular layer interneurons (MLIs) play an important role in cerebellar information processing by controlling Purkinje cell (PC) activity via inhibitory synaptic transmission. A local MLI network, constructed from both chemical and electrical synapses, is organized into spatially structured clusters that amplify feedforward and lateral inhibition to shape the temporal and spatial patterns of PC activity. Several recent in vivo studies indicate that such MLI circuits contribute not only to sensorimotor information processing, but also to precise motor coordination and cognitive processes. Here, we review current understanding of the organization of MLI circuits and their roles in the function of the mammalian cerebellum.
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The cerebellum is involved in motor learning, and long-term depression (LTD) at parallel fiber-to-Purkinje cell (PF-PC) synapses has been considered to be a primary cellular mechanism for motor learning. In addition, the contribution of norepinephrine (NE) to cerebellum-dependent learning paradigms has been reported. Thus, the roles of LTD and of NE in motor learning have been studied separately, and the relationship between the effects of NE and LTD remains unclear. ⋯ Here we found that specific agonists for β-AR or NE did not directly change synaptic transmission, but lowered the threshold for LTD induction at PF-PC synapses in the flocculus. In addition, protein kinase A (PKA), which is activated downstream of β-AR, facilitated the LTD induction. Altogether, these results suggest that NE facilitates LTD induction at PF-PC synapses in the flocculus by activating PKA through β-AR.
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In the cerebellum of neonatal mice, multiple climbing fibers (CFs) form excitatory synapses on each Purkinje cell (PC). Only one CF is strengthened in each PC from postnatal day 3 (P3) to P7, whereas the other weaker CFs are eliminated progressively from ∼P7 to ∼P11 (early phase of CF elimination) and from ∼P12 to ∼P17 (late phase of CF elimination). Type 1 metabotropic glutamate receptor (mGluR1) triggers a canonical pathway in PCs for the late phase of CF elimination. ⋯ By recording CF-mediated excitatory postsynaptic currents from PCs and immunostaining CF synaptic terminals, we found that significantly higher percentage of PCs with PLCβ3-KD remained multiply innervated by CFs in Aldoc (+) compartments after P12, which was accompanied by impaired elimination of somatic CF synapses and reduced dendritic CF translocation. In contrast, deletion of Aldoc had no effect on CF synapse elimination. These results suggest that PLCβ3 is required for the late phase of CF elimination in Aldoc (+) PCs.