Opposing actions of CRF-R1 and CB1 receptor on facial stimulation-induced MLI-PC plasticity in mouse cerebellar cortex

Abstract

Background Corticotropin-releasing factor (CRF) is the major neuromodulator orchestrating the stress response, and is secreted by neurons in various regions of the brain. Cerebellar CRF is released by afferents from inferior olivary neurons and other brainstem nuclei in response to stressful challenges, and contributes to modulation of synaptic plasticity and motor learning behavior via its receptors. We recently found that CRF modulates facial stimulation-evoked molecular layer interneuron-Purkinje cell (MLI-PC) synaptic transmission via CRF type 1 receptor (CRF-R1) in vivo in mice, suggesting that CRF modulates sensory stimulation-evoked MLI-PC synaptic plasticity. However, the mechanism of how CRF modulates MLI-PC synaptic plasticity is unclear. We investigated the effect of CRF on facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological methods. Results Facial stimulation at 1 Hz induced LTD of MLI-PC synaptic transmission under control conditions, but not in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by application of a selective CRF-R1 antagonist, BMS-763,534 (200 nM), but it was not restored by application of a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Blocking cannabinoid type 1 (CB1) receptor abolished the facial stimulation-induced MLI-PC LTD, and revealed a CRF-triggered MLI-PC long-term potentiation (LTP) via CRF-R1. Notably, either inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca2+ with cyclopiazonic acid (100 µM), completely prevented CRF-triggered MLI-PC LTP in mouse cerebellar cortex in vivo. Conclusions The present results indicated that CRF blocked sensory stimulation-induced opioid-dependent MLI-PC LTD by triggering MLI-PC LTP through CRF-R1/PKC and intracellular Ca2+ signaling pathway in mouse cerebellar cortex. These results suggest that activation of CRF-R1 opposes opioid-mediated cerebellar MLI-PC plasticity in vivo in mice.

Neuropeptides and Their Roles in the Cerebellum

“…Therefore, advances in functional studies of the cerebellar neuropeptides may provide a novel framework for a better understanding of the physiology and pathology of the cerebellum and pave a new path to develop novel potential therapeutic strategies for treating neurodegenerative and neuropsychiatric disorders. CF synapse elimination ↑ [27] Inhibitory synapse development ↑ [25,27] GrC and PC excitability ↑ [28] GABAergic transmission in PCs ↑↓ [29-31] Ionic plasticity ↑ [32] Paired-pulse facilitation ↑ [33] Neuroprotective effect ↑ [22,37] Neuroimmune modulation ↑ [38,39] Ataxic gait ↓ [23,36] CRF PC development ↑ [64,65] Presynaptic development in the cerebellar cortex ↑ [62,63] Glutamatergic neuron excitability in the interposed nucleus ↑ [43] PC excitability ↑ [47] LTD of PF-PC transmission ↑ [48] LTD of CF-PC transmission ↑ [49] LTP of CF-PC transmission ↑ [50] LTD between interneuron and PC ↓ [51] LTP of MF-GrC transmission ↑ [52] Motor control under challenging conditions ↑ [44] Motor performance ↑ [43] Motor learning ↓ [52,57] Ataxic symptoms ↓ [43] Cerebellar theta oscillations ↑ [101] The timing of TEC ↑ [101] Motor performance during a motor challenge ↑ [99] Arterial blood flow redistribution ↑ [100] Anxiolytic effect ↑ [102] TRH Migration and differentiation of GrCs ↑ [109] Dendritogenesis and neuritogenesis of PCs ↑ [109,110] Synaptogenesis ↑ [109] Neuronal excitability in the cerebellar cortex ↓ [112] Neuronal excitability in the interposed nucleus ↑ [108] LTD of P...…”

“…These results indicate that CRF may regulate the strength of excitatory inputs to PCs bidirectionally. Moreover, CRF can block facial stimulation-induced LTD at inhibitory synapses between the molecular layer interneurons and PCs by triggering long-term potentiation (LTP) at these synapses via CRFR1 and its underlying PKC signaling pathway [51]. In addition to the modulatory effects on synaptic inputs to PCs, GrC-specific knockout of CRFR1 has also been shown to affect MF-GrC transmissions, manifested by converting the high-frequency MF stimulationinduced LTP into LTD [52].…”