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.

Background Corticotropin-releasing factor (CRF) is an important neuromodulator in cerebellar cortex, which plays critical roles in modulating synaptic transmission and plasticity via its receptors. Activation of cannabinoid receptor 1 (CB1) controls the sensory stimulation-induced interneuron–Purkinje cell long-term depression (MLI-PC LTD) in mouse cerebellar cortex. However, the cellular actions of CRF on MLI-PC LTD are poor understand. We here investigated the effect of CRF on the facial stimulation-evoked MLI-PC long-term depression (LTD) in urethane-anesthetized mice by cell-attached recording technique and pharmacological method. Results Facial stimulation at 1Hz induced a LTD of MLI-PC synaptic transmission under control conditions, but it was not induced in the presence of CRF (100 nM). The CRF-abolished MLI-PC LTD was restored by a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM), but it was not restored by 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-R1 receptor activation-dependent MLI-PC long-term potentiation (LTP). However, the CRF-R1 receptor activation-dependent MLI-PC LTP was abolished by inhibition of protein kinase C (PKC) with chelerythrine (5 µM) or depletion of intracellular Ca2+ with cyclopiazonic acid (100 µM). Conclusions The present results indicate that CRF opposes the CB1 receptor-dependent MLI-PC LTD produced by the facial stimulation train, which may be caused by triggering a MLI-PC LTP through CRF-R1/PKC and intracellular Ca2+ signaling pathway in mouse cerebellar cortex. Our results suggest that CRF-R1 and CB1 receptor play oppose actions on facial stimulation-induced cerebellar MLI-PC plasticity in vivo in mice.