Inhibitory synaptic plasticity in the cerebellum.

Learning and memory within the brain are thought to be based on long lasting changes in synaptic efficacy. Purkinje neurones, which focus their output on descending projection pathways and constitute the sole inhibitory output from the cerebellum, display two forms of synaptic plasticity termed 'depolarisation-induced suppression of inhibition' (DSI) and 'rebound potentiation' (RP). Purkinje neurone depolarisation induces a rapid rise in [Ca2+ ]I triggering both the release of a retrograde transmitter and activation of a variety of protein kinases. The phenomena of DSI underlies a transient (lasting <60s) decrease in the mean frequency of mIPSCs, occurring immediately after stimulus cessation, while RP manifests itself as a robust increase in the mean amplitude of spontaneous and miniature inhibitory postsynaptic currents (IPSCs). The present study examined the relationship between pre- and postsynaptic plasticity during the induction phase of DSI and rebound potentiation in cultured cerebellar Purkinje neurones. Depolarisation caused an immediate decrease in the frequency of mIPSCs (lasting ~40s), followed by a transient increase in mIPSC frequency lasting approximately 5 minutes before recovering. A robust potentiation of the mean mIPSC amplitude was observed throughout all experiments and persisted for the duration of recording. The initial frequency decrease (DSI), was abolished by a specific group II mGluR antagonist, LY 341495, while the subsequent transient frequency potentiation was abolished by the specific N-methyl-D-aspartate receptor (NMDAR) antagonist, d-APV. Removal of extracellular sodium, the main current carrying ion through NMDARs, mimicked the application of d-APV by abolishing the frequency potentiation while having no effect on the induction of DSI. Immunocytochemical staining of mixed cerebellar preparations identified cerebellar basket/stellate cells as displaying immunoreactivity for NMDAR NR1 subunits but not mGluR2/3 at putative presynaptic release sites. These results provide the first evidence for, 1) the involvement of presynaptic NMDARs in the transient enhancement of GABA release during rebound potentiation and 2) the possibility that a novel group II mGluR splice variant/subtype underlies the induction of cerebellar DSI. A model is proposed to explain the relationship between DSI and rebound potentiation

Tonic Inhibition Enhances Fidelity of Sensory Information Transmission in the Cerebellar Cortex

Tonic inhibition is a key regulator of neuronal excitability and network function in the brain, but its role in sensory information processing remains poorly understood. The cerebellum is a favorable model system for addressing this question as granule cells, which form the input layer of the cerebellar cortex, permit high-resolution patch-clamp recordings in vivo, and are the only neurons in the cerebellar cortex that express the α6δ-containing GABA(A) receptors mediating tonic inhibition. We investigated how tonic inhibition regulates sensory information transmission in the rat cerebellum by using a combination of intracellular recordings from granule cells and molecular layer interneurons in vivo, selective pharmacology, and in vitro dynamic clamp experiments. We show that blocking tonic inhibition significantly increases the spontaneous firing rate of granule cells while only moderately increasing sensory-evoked spike output. In contrast, enhancing tonic inhibition reduces the spike probability in response to sensory stimulation with minimal effect on the spontaneous spike rate. Both manipulations result in a reduction in the signal-to-noise ratio of sensory transmission in granule cells and of parallel fiber synaptic input to downstream molecular layer interneurons. These results suggest that under basal conditions the level of tonic inhibition in vivo enhances the fidelity of sensory information transmission through the input layer of the cerebellar cortex

Inferior Olive HCN1 Channels Coordinate Synaptic Integration and Complex Spike Timing

Acknowledgments This work was supported by the Medical Research Council (G0501216), the Wellcome Trust (093295/Z/10/Z and 086602/Z/08/Z), and the BBSRC (Bb/H020284/1). We thank Paolo Puggioni for help with motion analysis and the IMPACT facility at the University of Edinburgh for imaging resources.Peer reviewe

Imaging learned fear circuitry in awake mice using fMRI

Functional magnetic resonance imaging (fMRI) of learned behaviour in ‘awake rodents’ provides the opportunity for translational preclinical studies into the influence of pharmacological and genetic manipulations on brain function. fMRI has recently been employed to investigate learned behaviour in awake rats. Here, this methodology is translated to mice, so that future fMRI studies may exploit the vast number of genetically modified mouse lines that are available. One group of mice was conditioned to associate a flashing light (conditioned stimulus, CS) with foot shock (PG; paired group), and another group of mice received foot shock and flashing light explicitly unpaired (UG; unpaired group). The blood oxygen level-dependent signal (proxy for neuronal activation) in response to the CS was measured 24 h later in awake mice from the PG and UG using fMRI. The amygdala, implicated in fear processing, was activated to a greater degree in the PG than in the UG in response to the CS. Additionally, the nucleus accumbens was activated in the UG in response to the CS. Because the CS signalled an absence of foot shock in the UG, it is possible that this region is involved in processing the safety aspect of the CS. To conclude, the first use of fMRI to visualise brain activation in awake mice that are completing a learned emotional task is reported. This work paves the way for future preclinical fMRI studies to investigate genetic and environmental influences on brain function in transgenic mouse models of disease and aging