GABAergic synaptic communication in the GABAergic and non-GABAergic cells in the deep cerebellar nuclei (original) (raw)
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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.
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...
The development of inhibitory synaptic specializations in the mouse deep cerebellar nuclei
Neuroscience, 2001
Using confocal laser scanning microscopy and immunohistochemistry, this study shows the complete morphological development of GABAergic synaptic contacts between Purkinje cells and neurons of the deep cerebellar nuclei of the mouse. Firstly, presynaptic varicosities visualized with antibodies against synaptophysin, synapsin or glutamic acid decarboxylase, were detected when the postsynaptic GABA(A) receptors were not yet aggregated in the membrane but had a diffuse cytoplasmic distribution, which indicated a lead in maturation of presynaptic terminals over target cells. Secondly, receptor aggregates developed suddenly after an initial week of diffuse expression and these clusters matured into more numerous and larger synaptic aggregates. During this postsynaptic maturation, the presynaptic varicosities develop into numerous and well-defined spots. As soon as both pre- and postsynaptic clusters were detectable, these sites are always colocalized. We therefore consider the aggregation...
Cerebellar Nuclei: Key Roles for Strategically Located Structures
The Cerebellum, 2010
With the exception of vestibular information, cerebellar nuclei represent the unique source of output of the cerebellar circuitry. The fastigial (FN), globose/emboliform (interpositus, IN), and dentate (DN) nuclei receive inhibitory GABAergic signals from Purkinje neurons and send back fibers to the cerebellar cortex. The numerous GABA-A inhibitory synapses between cerebellar cortex and cerebellar nuclei allow responses to high-frequency Purkinje cell firing . Cerebellar nuclei receive excitatory collaterals of mossy fibers and climbing fibers, especially via AMPA and NMDA receptors . A subset of small neurons in cerebellar nuclei project to the inferior olivary complex, providing a feedback to the inferior olive. Cerebellar nuclei thus integrate the converging excitatory and inhibitory signals to provide the final output of the cerebellar circuits. Each cerebellar nucleus has a separate somatotopic representation of the body . The projections to different cerebral cortical areas originate from distinct areas of cerebellar nuclei. In particular, the DN is spatially divided into a motor and nonmotor zone, with a closed loop from the nucleus to the cerebral cortex and back to the nucleus. Cerebellar nuclei control differentially the medial and lateral motor systems and their functions [4]. The vestibular and FN are concerned with the control of eye movements, control of head orientation, stance, and gait. FN can be functionally divided into rostral and caudal components [4, 5]. The rostral portion is involved in the control of somatic musculature, head orientation, and eye-gaze shifts [4]. The caudal FN plays key roles in saccade generation and smooth pursuit [6]. The IN is particularly active during the modulation of various reflexes and sensory feedback [7]. The eyeblink responses are typically associated with a modulation of activity in behaving animals [8]. The intermediate cortex and the IN fire in relation to the antagonist muscle group [9, 10], in agreement with a role in damping the limb oscillations and compensation of errors [11]. The IN participates in the excitability of the stretch reflexes [12]
PloS one, 2012
Inhibitory interneurons in the cerebellar granular layer are more heterogeneous than traditionally depicted. In contrast to Golgi cells, which are ubiquitously distributed in the granular layer, small fusiform Lugaro cells and globular cells are located underneath the Purkinje cell layer and small in number. Globular cells have not been characterized physiologically. Here, using cerebellar slices obtained from a strain of gene-manipulated mice expressing GFP specifically in GABAergic neurons, we morphologically identified globular cells, and compared their synaptic activity and monoaminergic influence of their electrical activity with those of small Golgi cells and small fusiform Lugaro cells. Globular cells were characterized by prominent IPSCs together with monosynaptic inputs from the axon collaterals of Purkinje cells, whereas small Golgi cells or small fusiform Lugaro cells displayed fewer and smaller spontaneous IPSCs. Globular cells were silent at rest and fired spike dischar...
GlyT2+ Neurons in the Lateral Cerebellar Nucleus
The Cerebellum, 2010
The deep cerebellar nuclei (DCN) are a major hub in the cerebellar circuitry but the functional classification of their neurons is incomplete. We have previously characterized three cell groups in the lateral cerebellar nucleus: large non-GABAergic neurons and two groups of smaller neurons, one of which express green fluorescence protein (GFP) in a GAD67/GFP mouse line and is therefore GABAergic. However, as a substantial number of glycinergic and glycine/GABA co-expressing neurons have been described in the DCN, this classification needed to be refined by considering glycinergic neurons. To this end we took advantage of a glycine transporter isoform 2 (GlyT2)-eGFP mouse line that allows identification of GlyT2expressing, presumably glycinergic neurons in living cerebellar slices and compared their electrophysiological properties with previously described DCN neuron populations. We found two electrophysiologically and morphologically distinct sets of GlyT2-expressing neurons in the lateral cerebellar nucleus. One of them showed electrophysiological similarity to the previously characterized GABAergic cell group. The second GlyT2+ cell population, however, differed from all other so far described neuron types in DCN in that the cells (1) are intrinsically silent in slices and only fire action potentials upon depolarizing current injection and (2) have a projecting axon that was often seen to leave the DCN and project in the direction of the cerebellar cortex. Presence of this so far undescribed DCN neuron population in the lateral nucleus suggests a direct inhibitory pathway from the DCN to the cerebellar cortex.
Synchrony is Key: Complex Spike Inhibition of the Deep Cerebellar Nuclei
The Cerebellum, 2015
The control of deep cerebellar nuclear (DCN) neuronal firing is central to cerebellar function, but is not well understood. The large majority of synapses onto DCN neurons derive from Purkinje cells (PCs), suggesting that PC activity is an important determinant of DCN firing; however, PCs fire both simple and complex spikes (CSs), and little is known about how the latter's action affects DCN activity. Thus, here we explored the effects of CSs on DCN activity. CSs were recorded from PC arrays along with individual DCN neurons. Presumed synaptically connected PC-DCN cell pairs were identified using CS-triggered correlograms of DCN activity, which also showed that CS activity was associated with a predominantly inhibitory effect on DCN activity. The strength of the CS effect varied as a function of synchrony, such that isolated CSs produced only weak inhibition of DCN activity, whereas highly synchronous CSs caused a larger drop in firing levels. Although the present findings were obtained in anesthetized animals, similar CS synchrony levels exist in awake animals, and changes in synchrony level have been observed in association with movements in awake animals. Thus, the present data suggest that synchronous CS activity may be a mechanism for shaping DCN output related to motor commands.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018
Perineuronal nets (PNNs), composed mainly of chondroitin sulfate proteoglycans (CSPGs), are the extracellular matrix that surrounds cell bodies, proximal dendrites, and axon initial segments of adult CNS neurons. PNNs are known to regulate neuronal plasticity, although their physiological roles in cerebellar functions have yet to be elucidated. Here, we investigated the contribution of PNNs to GABAergic transmission from cerebellar Purkinje cells (PCs) to glutamatergic neurons in the deep cerebellar nuclei (DCN) in male mice by recording inhibitory postsynaptic currents (IPSCs) from cerebellar slices, in which PNNs were depleted with chondroitinase ABC (ChABC). We found that PNN depletion increased the amplitude of evoked IPSCs and enhanced the paired-pulse depression. ChABC treatment also facilitated spontaneous IPSCs and increased the miniature IPSC frequency without changing not only the amplitude but also the density of PC terminals, suggesting that PNN depletion enhances presyn...
2021
Circuitry of the cerebellar cortex is regionally and functionally specialized. Unipolar brush cells (UBCs), and Purkinje cell (PC) synapses made by axon collaterals in the granular layer, are both enriched in areas that control balance and eye-movement. Here we find a link between these specializations: PCs preferentially inhibit mGluR1-expressing UBCs that respond to mossy fiber inputs with long lasting increases in firing, but PCs do not inhibit mGluR1-lacking UBCs. PCs inhibit about 29% of mGluR1-expressing UBCs by activating GABAAreceptors (GABAARs) and inhibit almost all mGluR1-expressing UBCs by activating GABABRs. PC to UBC synapses allow PC output to regulate the input layer of the cerebellar cortex in diverse ways. GABAAR-mediated feedback is fast, unreliable, noisy, and suited to linearizing input-output curves and decreasing gain. Slow GABABR-mediated inhibition allows elevated PC activity to sharpen the input-output transformation of UBCs, and allows dynamic inhibitory f...