Tonic Activation of GABA_B Receptors Reduces Release Probability at Inhibitory Connections in the Cerebellar Glomerulus

Abstract

In the cerebellum, granule cells are inhibited by Golgi cells through GABAergic synapses generating complex responses involving both phasic neurotransmitter release and the establishment of ambient γ-aminobutyric acid (GABA) levels. Although at this synapse the mechanisms of postsynaptic integration have been clarified to a considerable extent, the mechanisms of neurotransmitter release remained largely unknown. Here we have investigated the quantal properties of release during repetitive neurotransmission, revealing that tonic GABAB receptor activation by ambient GABA regulates release probability. Blocking GABAB receptors with CGP55845 enhanced the first inhibitory postsynaptic current (IPSC) and short-term depression in a train while reducing trial-to-trial variability and failures. The changes caused by CGP55845 were similar to those caused by increasing extracellular Ca2+ concentration, in agreement with a presynaptic GABAB receptor modulation of release probability. However, the slow tail following IPSC peak demonstrated a remarkable temporal summation and was not modified by CGP55845 or extracellular Ca2+ increase. This result shows that tonic activation of presynaptic GABAB receptors by ambient GABA selectively regulates the onset of inhibition bearing potential consequences for the dynamic regulation of signal transmission through the mossy fiber–granule cell pathway of the cerebellum.

Hebbian Spike-Timing Dependent Plasticity at the Cerebellar Input Stage

“…While st-LTP was induced when EPSP led AP, st-LTD was induced when AP led EPSP according to the Hebbian principle of coincidence detection between presynaptic and postsynaptic activity. In this respect, mossy fiber-granule cell STDP is similar to that observed at different synapses mostly located in the neocortex and hippocampus (Magee and Johnston, 1997;Markram et al, 1997;Bi and Poo, 1998 first evidence that Hebbian STDP occurs in the cerebellum because previous observations only reported either non-Hebbian STDP at the parallel fiber-Purkinje-like cell synapse (Safo and Regehr, 2008;Piochon et al, 2012) or anti-Hebbian STDP at the corresponding synapses of cerebellum-like structures (Bell et al, 1997;Tzounopoulos et al, 2004;Wu et al, 2015). It should be noted that, different from Purkinje cells, granule cells show a rapid and complete spike back-propagation into the dendrites (Diwakar et al, 2009;Dover et al, 2016), so that information about AP generation can be faithfully transmitted to synaptic sites providing a key requirement for Hebbian STDP.…”

“…The error introduced in amplitude measurement by the failures, which have non-0 amplitude due to the indirect response, was eliminated by setting the amplitude of the indirect responses to 0 . To investigate the expression mechanism of STDP D'Errico et al, 2009;Mapelli et al, 2009), a simplified version of quantal analysis was performed by measuring the mean and SD of EPSC amplitude. All measurements were performed over N ϭ 100 contiguous EPSCs minimizing errors introduced by small samples (data not shown).…”

“…STDP typically requires repetitive EPSP/AP pairing at low frequency with a "time window" of Ͻ100 ms and shows a sharp transition between st-LTP and st-LTD; its magnitude is sensitive to the EPSP/AP interval (STDP degrades toward the edges of the time window) and depends on spike back-propagation and membrane depolarization (Markram et al, 1997;Bi and Poo, 1998;Zhang et al, 1998;Stuart and Häusser, 2001;Celikel et al, 2004;Sjöström and Häusser, 2006). STDP is defined Hebbian when potentiation occurs with EPSPs leading APs (st-LTP) and depression occurs with APs leading EPSPs (st-LTD) (Hebb, 1949); vice versa, it is called anti-Hebbian (in both cases, spike back-propagation into the dendrites down to the synapses is needed, otherwise STDP in non-Hebbian).…”

Granular Layer Neurons Control Cerebellar Neurovascular Coupling Through an NMDA Receptor/NO-Dependent System

“…Acute rat cerebellar slices were obtained as reported previously (D'Angelo et al, 1995;Armano et al, 2000;Mapelli et al, 2009). Briefly, 17-to 23-d-old Wistar rats of both sexes were anesthetized with halothane (Sigma-Aldrich) and killed by decapitation.…”

The Mammalian Interaural Time Difference Detection Circuit Is Differentially Controlled by GABAB Receptors during Development

“…We have previously shown that, in the lateral superior olive (LSO), GABA B R activation by retrogradely released GABA regulates the balance of excitation and inhibition and thereby adjusts the sensitivity of these neurons to interaural intensity differences (Magnusson et al, 2008). Furthermore, presynaptic GABA B Rs have been implicated in decreasing short-term synaptic depression and might thereby improve faithful synaptic transmission for the represen-tation of sound structure (Brenowitz et al, 1998;Mapelli et al, 2009). Preliminary immunostainings have revealed that in the auditory brainstem GABA B Rs are not only present before hearing onset, when the MNTB releases both GABA and glycine, but also in adult animals, when the MNTB input has become glycinergic (Heise et al, 2005;Hilbig et al, 2007).…”