Cerebellar globular cells receive monoaminergic excitation and monosynaptic inhibition from Purkinje cells (original) (raw)
Related papers
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014
The principal neurons of the cerebellar nuclei (CN), the sole output of the olivo-cerebellar system, receive a massive inhibitory input from Purkinje cells (PCs) of the cerebellar cortex. Morphological evidence suggests that CN principal cells are also contacted by inhibitory interneurons, but the properties of this connection are unknown. Using transgenic, tracing, and immunohistochemical approaches in mice, we show that CN interneurons form a large heterogeneous population with GABA/glycinergic phenotypes, distinct from GABAergic olive-projecting neurons. CN interneurons are found to contact principal output neurons, via glycine receptor (GlyR)-enriched synapses, virtually devoid of the main GABA receptor (GABAR) subunits α1 and γ2. Those clusters account for 5% of the total number of inhibitory receptor clusters on principal neurons. Brief optogenetic stimulations of CN interneurons, through selective expression of channelrhodopsin 2 after viral-mediated transfection of the flexe...
Brain Research, 1986
Purkinje cell degeneration (pcd) mutant mice, 3-4 months old, were used to identify and quantify the non-Purkinje cell GABAergic innervation of deep cerebellar nuclei. Glutamic acid decarboxylase (GAD) immunoreactive structures appeared as dark dots throughout the 4 nuclei. Ultrastructural examination confirmed that each dot corresponded to an axon terminal. GAD-labeled boutons were large, contained tightly packed flattened vesicles and established Gray type II synapses with all nuclear neuronal populations. Thus, cytological criteria did not distinguish between Purkinje cell and non-Purkinje cell GAD-positive nerve terminals, since they shared many common features. The number of GAD-immunoreactive axon terminals in the deep nuclei of pcd cerebella was compared to that of normal C57BL mice. Despite an almost complete disappearance of Purkinje cells in the pcd mouse (less than 0.05% of these neurons remained in the mutants), the surface density of GAD-positive nerve terminals in the deep nuclear region was 37% of control value. Taking into account a volumetric decrease of 58% for the deep nuclei of the mutant cerebellum, we estimated the percentage of GAD-positive boutons innervating these nuclei to be 15% of normal values. This important residual innervation of the deep nuclei might arise from local GABAergic neurons, which were identified in the normal and mutant cerebella by immunostaining with an anti-GABA antibody.
2008
Abstract—The deep cerebellar nuclei (DCN) are the final integrative units of the cerebellar network. The strongest single afferent to the DCN is formed by GABAergic Purkinje neuron axons whose synapses constitute the majority of all synapses in the DCN, with their action strongly regulating the intrinsic activity of their target neurons. Although this is well established, it remains unclear whether all DCN cell groups receive a functionally similar inhibitory input.
Neonatal Rat Cerebellar Granule and Purkinje Neurons in Culture Express Different GABA A Receptors
European Journal of Neuroscience, 1995
We have established a culture system for microexplants of rat cerebellar cortical tissue in which cells develop morphologically, express type-A receptors for the inhibitory neurotransmitter y-aminobutyric acid (GABA) and form GABAergic synaptic connections. Criteria of cell size and shape allow reliable identification of granule and Purkinje neurons, criteria confirmed by studies of the binding of antibodies to calbindin D28K and GABA. Both granule and Purkinje neurons express GABAA receptors, but granule neurons fall into two classes in terms of their sensitivity. Granule neurons which do not show spontaneous synaptic currents are relatively insensitive to GABA, while granule neurons with synaptic currents are much more sensitive. The responses of Purkinje neurons to applications of 1 pM GABA are relatively insensitive to Zn2+ ions (10 pM), and are potentiated by chlordiazepoxide (100 pM) and La3+ ions (100 pM). Responses of innervated granule neurons, on the other hand, are blocked more strongly by Zn2+ ions, are less affected by chlordiazepoxide and are equally potentiated by La3+ ions. Hence these cultures provide a source of identifiable, functionally innervated cells which express distinct types of GABAA receptors.
Clusters of cerebellar Purkinje cells control their afferent climbing fiber discharge
Proceedings of the National Academy of Sciences of the United States of America, 2013
Climbing fibers, the projections from the inferior olive to the cerebellar cortex, carry sensorimotor error and clock signals that trigger motor learning by controlling cerebellar Purkinje cell synaptic plasticity and discharge. Purkinje cells target the deep cerebellar nuclei, which are the output of the cerebellum and include an inhibitory GABAergic projection to the inferior olive. This pathway identifies a potential closed loop in the olivo-cortico-nuclear network. Therefore, sets of Purkinje cells may phasically control their own climbing fiber afferents. Here, using in vitro and in vivo recordings, we describe a genetically modified mouse model that allows the specific optogenetic control of Purkinje cell discharge. Tetrode recordings in the cerebellar nuclei demonstrate that focal stimulations of Purkinje cells strongly inhibit spatially restricted sets of cerebellar nuclear neurons. Strikingly, such stimulations trigger delayed climbing-fiber input signals in the stimulated Purkinje cells. Therefore, our results demonstrate that Purkinje cells phasically control the discharge of their own olivary afferents and thus might participate in the regulation of cerebellar motor learning. motor control | olivo-cerebellar loop | complex spikes T he cerebellar cortex is involved in a wealth of functions, from the control of posture to higher cognitive processes (1-3). Purkinje cells (PCs) are key processing units of the cerebellar cortex (4): each PC receives more than 175,000 parallel fiber synaptic inputs carrying information about the ongoing sensorymotor context. It also receives a single inferior olive afferent, the climbing fiber, which triggers a complex spike (CS), modulates PC firing (5), controls synaptic input plasticity, and has been proposed to carry error and clock signals to the cerebellum (2, 4-8). PCs are grouped in multiple parasagittal microzones, each receiving projections from separate areas of the inferior olive and projecting to subregions of the cerebellar nuclei (CN) (9-12). In the CN, PCs make inhibitory contacts on excitatory neurons that project to various premotor areas and propagate cerebellar computations to the motor system. Anatomical evidence indicates that PC terminals also contact CN inhibitory neurons that target inferior olive cells . This nucleoolivary pathway is topographically organized in multiple parallel projections to the inferior olive subnuclei (15), suggesting the existence of closed olivary-cortico-nuclear loops. Therefore, the discharge of a population of PCs in a microzone might not only shape the output of the cerebellum but also control its afferent climbing-fiber signal. Previous studies have shown that stimulation of the nucleo-olivary pathway significantly reduces olivary cell firing (16-18) and that pharmacological and genetic manipulations of PCs or olivary cell activity induce reciprocal modulations of the firing rate of PCs and climbing fibers .
Journal of Neuroscience, 2013
The function of inhibitory interneurons within brain microcircuits depends critically on the nature and properties of their excitatory synaptic drive. Golgi cells (GoCs) of the cerebellum inhibit cerebellar granule cells (GrCs) and are driven both by feedforward mossy fiber (mf) and feedback GrC excitation. Here, we have characterized GrC inputs to GoCs in rats and mice. We show that, during sustained mf discharge, synapses from local GrCs contribute equivalent charge to GoCs as mf synapses, arguing for the importance of the feedback inhibition. Previous studies predicted that GrC-GoC synapses occur predominantly between parallel fibers (pfs) and apical GoC dendrites in the molecular layer (ML). By combining EM and Ca 2ϩ imaging, we now demonstrate the presence of functional synaptic contacts between ascending axons (aa) of GrCs and basolateral dendrites of GoCs in the granular layer (GL). Immunohistochemical quantification estimates these contacts to be ϳ400 per GoC. Using Ca 2ϩ imaging to identify synaptic inputs, we show that EPSCs from aa and mf contacts in basolateral dendrites display similarly fast kinetics, whereas pf inputs in the ML exhibit markedly slower kinetics as they undergo strong filtering by apical dendrites. We estimate that approximately half of the local GrC contacts generate fast EPSCs, indicating their basolateral location in the GL. We conclude that GrCs, through their aa contacts onto proximal GoC dendrites, define a powerful feedback inhibitory circuit in the GL.
Integration and regulation of glomerular inhibition in the cerebellar granular layer circuit
Frontiers in Cellular Neuroscience, 2014
Inhibitory synapses can be organized in different ways and be regulated by a multitude of mechanisms. One of the best known examples is provided by the inhibitory synapses formed by Golgi cells onto granule cells in the cerebellar glomeruli. These synapses are GABAergic and inhibit granule cells through two main mechanisms, phasic and tonic. The former is based on vesicular neurotransmitter release, the latter on the establishment of tonic γ-aminobutyric acid (GABA) levels determined by spillover and regulation of GABA uptake. The mechanisms of post-synaptic integration have been clarified to a considerable extent and have been shown to differentially involve α1 and α6 subunit-containing GABA-A receptors. Here, after reviewing the basic mechanisms of GABAergic transmission in the cerebellar glomeruli, we examine how inhibition controls signal transfer at the mossy fiber-granule cell relay. First of all, we consider how vesicular release impacts on signal timing and how tonic GABA levels control neurotransmission gain. Then, we analyze the integration of these inhibitory mechanisms within the granular layer network. Interestingly, it turns out that glomerular inhibition is just one element in a large integrated signaling system controlled at various levels by metabotropic receptors. GABA-B receptor activation by ambient GABA regulates glutamate release from mossy fibers through a pre-synaptic cross-talk mechanisms, GABA release through pre-synaptic auto-receptors, and granule cell input resistance through post-synaptic receptor activation and inhibition of a K inward-rectifier current. Metabotropic glutamate receptors (mGluRs) control GABA release from Golgi cell terminals and Golgi cell input resistance and autorhythmic firing. This complex set of mechanisms implements both homeostatic and winner-take-all processes, providing the basis for fine-tuning inhibitory neurotransmission and for optimizing signal transfer through the cerebellar cortex.