Enhancement of GABA release through endogenous activation of axonal GABA(A) receptors in juvenile cerebellum.

Recent evidence indicates the presence of presynaptic GABA(A) receptors (GABA(A)Rs) in the axon domain of several classes of central neurons, including cerebellar basket and stellate cells. Here, we investigate the possibility that these receptors could be activated in the absence of electrical or chemical stimulation. We find that low concentrations of GABA increase the frequency of miniature GABAergic synaptic currents. Submaximal concentrations of a GABA(A)R blocker, gabazine, decrease both the miniature current frequency and the probability of evoked GABA release. Zolpidem, an agonist of the benzodiazepine binding site, and NO-711 (1-[2-[[(diphenylmethylene)imino]oxy]ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride), a blocker of GABA uptake, both increase the frequency of miniature currents. These effects occur up to postnatal day 14, but not later. Immunohistochemistry indicates the presence of alpha1-containing GABA(A)Rs in interneuron presynaptic terminals with a similar age dependence. We conclude that, under resting conditions, axonal GABA(A)Rs are significantly activated, that this activation results in enhanced GABA release, and that it can be augmented by increasing the affinity of GABA(A)Rs or reducing GABA uptake. Our findings suggest the existence of a positive-feedback mechanism involving presynaptic GABA(A)Rs that maintains a high release rate and a high local GABA concentration in the immature cerebellar network.

T-type and L-type Ca2+ conductances define and encode the bimodal firing pattern of vestibulocerebellar unipolar brush cells.

Cerebellar unipolar brush cells (UBCs) are glutamatergic interneurons that receive direct input from vestibular afferents in the form of a unique excitatory synapse on their dendritic brush. UBCs constitute independent relay lines for vestibular signals, and their inherent properties most likely determine how vestibular activity is encoded by the cerebellar cortex. We now demonstrate that UBCs are bimodal cells; they can either fire high-frequency bursts of action potentials when stimulated from hyperpolarized potentials or discharge tonically during sustained depolarizations. The two functional states can be triggered by physiological-like activity of the excitatory input and are encoded by distinct Ca2+-signaling systems. By combining complementary strategies, consisting of molecular and electrophysiological analysis and of ultrafast acousto-optical deflector-based two-photon imaging, we unraveled the identity and the subcellular localization of the Ca2+ conductances activating in each mode. Fast inactivating T-type Ca2+ channels produce low-threshold spikes, which trigger the high-frequency bursts and generate powerful Ca2+ transients in the brush and, to a much lesser extent, in the soma. The tonic firing mode is encoded by a signalization system principally composed of L-type channels. Ca2+ influx during tonic firing produces a linear representation of the spike rate of the cell in the form of a widespread and sustained Ca2+ concentration increase and regulates cellular excitability via BK potassium channels. The bimodal firing pattern of UBCs may underlie different coding strategies of the vestibular input by the cerebellum, thus likely increasing the computational power of this structure.

Developmental changes in parvalbumin regulate presynaptic Ca2+ signaling.

Certain interneurons contain large concentrations of specific Ca2+-binding proteins (CBPs), but consequences on presynaptic Ca2+ signaling are poorly understood. Here we show that expression of the slow CBP parvalbumin (PV) in cerebellar interneurons is cell specific and developmentally regulated, leading to characteristic changes in presynaptic Ca2+ dynamics (Ca(i)). Using whole-cell recording and fluorescence imaging, we studied action potential-evoked Ca(i) transients in axons of GABA-releasing interneurons from mouse cerebellum. At early developmental stages [postnatal days 10-12 (P10-P12)], decay kinetics were significantly faster for basket cells than for stellate cells, whereas at P19-P21 both interneurons displayed fast decay kinetics. Biochemical and immunocytochemical analysis showed parallel changes in the expression levels and cellular distribution of PV. By comparing wild-type and PV(-/-) mice, PV was shown to accelerate the initial decay of action potential-evoked Ca(i) signals in single varicosities and to introduce an additional slow phase that summates during bursts of action potentials. The fast initial Ca(i) decay accounts for a previous report that PV elimination favors synaptic facilitation. The slow decay component is responsible for a pronounced, PV-dependent, delayed transmitter release that we describe here at interneuron-interneuron synapses after presynaptic bursts of action potentials. Numerical simulations account for the effect of PV on Ca(i) kinetics, allow estimates for the axonal PV concentration (approximately 150 microm), and predict the time course of volume-averaged Ca(i) in the absence of exogenous buffer. Overall, PV arises as a major contributor to presynaptic Ca(i) signals and synaptic integration in the cerebellar cortex.

Electrical coupling mediates tunable low-frequency oscillations and resonance in the cerebellar Golgi cell network.

Tonic motor control involves oscillatory synchronization of activity at low frequency (5-30 Hz) throughout the sensorimotor system, including cerebellar areas. We investigated the mechanisms underpinning cerebellar oscillations. We found that Golgi interneurons, which gate information transfer in the cerebellar cortex input layer, are extensively coupled through electrical synapses. When depolarized in vitro, these neurons displayed low-frequency oscillatory synchronization, imposing rhythmic inhibition onto granule cells. Combining experiments and modeling, we show that electrical transmission of the spike afterhyperpolarization is the essential component for oscillatory population synchronization. Rhythmic firing arises in spite of strong heterogeneities, is frequency tuned by the mean excitatory input to Golgi cells, and displays pronounced resonance when the modeled network is driven by oscillating inputs. In vivo, unitary Golgi cell activity was found to synchronize with low-frequency LFP oscillations occurring during quiet waking. These results suggest a major role for Golgi cells in coordinating cerebellar sensorimotor integration during oscillatory interactions.