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In mammalian brains, gamma-amino butyric acid (GABA) is the most ubiquitous inhibitory neurotransmitter and neuromodulator. The G(i/o) protein-coupled GABA receptor termed B-type GABA receptor (GABA(B)R) has been recognized as one of the major mediators of the inhibitory effects of GABA. Several years ago, Hirono et al. and our group independently found that GABA(B)R mediates non-inhibitory effects in cerebellar Purkinje cells. In this cell type, GABA(B)R co-localizes with type-1 metabotropic glutamate receptor (mGluR1), a G(q/11) protein-coupled receptor around the postsynaptic membrane of the excitatory synapses. At that site, GABA(B)R is not exposed to the direct bombardment of GABA released from the terminals of inhibitory neurons. Instead, the receptor may sense a low concentration of GABA and Ca(2+) usually contained in the extracellular fluid and a relatively high concentration of GABA spilt over from the neighboring active inhibitory synapses. In response to these ambient ligands, GABA(B)R increases the ligand affinity of mGluR1 independently of G(i/o) protein and augments mGluR1-coupled intracellular signaling via G(i/o) protein. These GABA(B)R-mediated modulations may facilitate mGluR1-mediated neuronal responses including cerebellar long-term depression, a form of synaptic plasticity crucial for cerebellar motor learning. In this article, we present current knowledge on a new role of GABA(B)R as an ambience-dependent regulator of synaptic signaling., (Copyright 2010 Elsevier Inc. All rights reserved.)

Marijuana affects neural functions through the binding of its active component (Delta(9)-THC) to cannabinoid receptors in the CNS. Recent studies have elucidated that endogenous ligands for cannabinoid receptors, endocannabinoids, serve as retrograde messengers at central synapses. Endocannabinoids are produced on demand in activity-dependent manners and released from postsynaptic neurons. The released endocannabinoids travel backward across the synapse, activate presynaptic CB1 cannabinoid receptors, and modulate presynaptic functions. Retrograde endocannabinoid signaling is crucial for certain forms of short-term and long-term synaptic plasticity at excitatory or inhibitory synapses in many brain regions, and thereby contributes to various aspects of brain function including learning and memory. Molecular identities of the CB1 receptor and enzymes involved in production and degradation of endocannabinoids have been elucidated. Anatomical studies have demonstrated unique distributions of these molecules around synapses, which provide morphological bases for the roles of endocannabinoids as retrograde messengers. CB1-knockout mice exhibit various behavioral abnormalities and multiple defects in synaptic plasticity, supporting the notion that endocannabinoid signaling is involved in various aspects of neural function. In this review article, the authors describe molecular mechanisms of the endocannabinoid-mediated synaptic modulation and its possible physiological significance.

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]

Functional neural circuit formation during postnatal development involves the elimination of early-formed redundant synapses. In the neonatal mouse cerebellum, each Purkinje cell is innervated by multiple climbing fibers (CFs). Their synaptic strengths are initially uniform but one CF strengthens relative to other CFs during the first postnatal week. Then the weaker CFs are eliminated during the second postnatal week. Projections from the retina to the lateral geniculate nucleus (LGN) undergo similar developmental changes, that is the elimination of the majority of inputs and strengthening of a few afferents that remain. Recent studies have clarified that in both cerebellum and LGN, synapse refinement consists of multiple phases and that distinct types of neural activity drive synaptic remodeling in each developmental phase. [Copyright &y& Elsevier]

Endocannabinoids mediate retrograde signaling and modulate synaptic transmission in various regions of the CNS. Depolarization-induced elevation of intracellular Ca2+ concentration causes endocannabinoid- mediated suppression of excitatory/inhibitory synaptic transmission. Activation of Gq/11-coupled receptors including group I metabotropic glutamate receptors (mGluRs) also causes endocannabinoid-mediated suppression of synaptic transmission. However, precise mechanisms of endocannabinoid production initiated by physiologically relevant synaptic activity remain to be determined. To address this problem, we made whole-cell recordings from Purkinje cells (PCs) in mouse cerebellar slices and examined their excitatory synapses arising from climbing fibers (CFs) and parallel fibers (PFs). We first characterized three distinct modes to induce endocannabinoid release by analyzing CF to PC synapses. The first mode is strong activation of mGluR subtype 1 (mGluR1)-phospholipase C (PLC)β4 cascade without detectable Ca2+ elevation. The second mode is Ca2+ elevation to a micromolar range without activation of the mGluR1-PLCβ4 cascade. The third mode is the Ca2+-assisted mGluR1-PLCβ4 cascade that requires weak mGluR1 activation and Ca2+ elevation to a submicromolar range. By analyzing PF to PC synapses, we show that the third mode is essential for effective endocannabinoid release from PCs by excitatory synaptic activity. Furthermore, our biochemical analysis demonstrates that combined weak mGluR1 activation and mild depolarization in PCs effectively produces 2-arachidonoylglycerol (2-AG), a candidate of endocannabinoid, whereas either stimulus alone did not produce detectable 2-AG. Our results strongly suggest that under physiological conditions, excitatory synaptic inputs to PCs activate the Ca2+-assisted mGluR1-PLCβ4 cascade, and thereby produce 2-AG, which retrogradely modulates synaptic transmission to PCs. [ABSTRACT FROM AUTHOR]

Abstract In the mammalian CNS, the peptide hormone insulin-like growth factor-I (IGF-I) is synthesized in a certain subset of neurons and, it has been suggested, serves as a local neurotrophic factor. A postnatal increase in the expression of IGF-I and the type-1 IGF receptors (IGFR1) in the cerebellar cortex and its related brain regions indicates that developing cerebellar Purkinje cells (PC) may be an important target of IGF-I. However, little is known about how IGF-I influences PC development. Here we addressed this question, using a reduced environment of cerebellar neuron culture derived from perinatal mice. IGF-I exogenously applied at a physiological concentration (10 nm) greatly promoted the dendritic growth and survival of the PCs. By contrast, IGF-I only slightly promoted the somatic growth and little affected the maturation of the electrophysiological excitability of the PCs. The closely related hormone insulin had weaker promoting effects than did IGF-I. IGF-I appeared to at least bind to IGFR1 and to up-regulate the signalling pathways involving the phosphoinositide 3-kinase (PI3-K), mitogen-activated protein kinase (MAPK), p38 kinase (p38K), and an unknown signalling molecule(s). These signalling pathways may be coupled to the individual aspects of PC development in different manners and this may explain the difference in effects of IGF-I among these aspects. These findings suggest that IGF-I serves as a promoting factor for PC development, particularly postnatal survival and dendritic growth. [ABSTRACT FROM AUTHOR]