Corticotropin-releasing factor (CRF) is an important neuromodulator in central nervous system that modulates neuronal activity via its receptors during stress responses. In cerebellar cortex, CRF modulates the simple spike (SS) firing activity of Purkinje cells (PCs) has been previously demonstrated, whereas the effect of CRF on the molecular layer interneuron (MLI)–PC synaptic transmission is still unknown. In this study, we examined the effect of CRF on the facial stimulation–evoked cerebellar cortical MLI-PC synaptic transmission in urethane-anesthetized mice by in vivo cell-attached recording, neurobiotin juxtacellular labeling, immunohistochemistry techniques, and pharmacological method. Cell-attached recordings from cerebellar PCs showed that air-puff stimulation of ipsilateral whisker pad evoked a sequence of tiny parallel fiber volley (N1) followed by MLI-PC synaptic transmission (P1). Microapplication of CRF in cerebellar cortical molecular layer induced increases in amplitude of P1 and pause of SS firing. The CRF decreases in amplitude of P1 waveform were in a dose-dependent manner with the EC50 of 241 nM. The effects of CRF on amplitude of P1 and pause of SS firing were abolished by either a non-selective CRF receptor antagonist, α-helical CRF-(9-14), or a selective CRF-R1 antagonist, BMS-763534 (BMS, 200 nM), but were not prevented by a selective CRF-R2 antagonist, antisauvagine-30 (200 nM). Notably, application CRF not only induced a significant increase in spontaneous spike firing rate, but also produced a significant increase in the number of the facial stimulation–evoked action potential in MLIs. The effect of CRF on the activity of MLIs was blocked by the selective CRF-R1 antagonist, and the MLIs expressed the CRF-R1 imunoreactivity. These results indicate that CRF increases excitability of MLIs via CRF-R1, resulting in an enhancement of the facial stimulation–evoked MLI-PC synaptic transmission in vivo in mice.

Acute ethanol overdose can induce dysfunction of cerebellar motor regulation and cerebellar ataxia. In this study, we investigated the effect of ethanol on facial stimulation-evoked inhibitory synaptic responses in cerebellar Purkinje cells (PCs) in urethane-anesthetized mice, using in vivo patch-clamp recordings. Under voltage-clamp conditions, ethanol (300 mM) decreased the amplitude, half-width, rise time and decay time of facial stimulation-evoked outward currents in PCs. The ethanol-induced inhibition of facial stimulation-evoked outward currents was dose-dependent, with an IC50 of 148.5 mM. Notably, the ethanol-induced inhibition of facial stimulation-evoked outward currents were significantly abrogated by cannabinoid receptor 1 (CB1) antagonists, AM251 and O-2050, as well as by the CB1 agonist WIN55212-2. Moreover, the ethanol-induced inhibition of facial stimulation-evoked outward currents was prevented by cerebellar surface perfusion of the PKA inhibitors H-89 and Rp-cAMP, but not by intracellular administration of the PKA inhibitor PKI. Our present results indicate that ethanol inhibits the facial stimulation-evoked outward currents by activating presynaptic CB1 receptors via the PKA signaling pathway. These findings suggest that ethanol overdose impairs sensory information processing, at least in part, by inhibiting GABA release from molecular layer interneurons onto PCs.

Spinal cord injury (SCI) often represents a condition of permanent neurologic deficit. It has been possible to understand and delineate the mechanisms contributing to loss of function following primary injury. The clinicians might hope to improve the outcome in SCI injury by designing treatment strategies that could target these secondary mechanisms of response to injury. However, the approaches like molecular targeting of the neurons or surgical interventions have yielded very limited success till date. In recent times, a great thrust is put on to the cellular transplantation mode of treatment strategies to combat SCI problems so as to gain maximum functional recovery. In this review, we discuss about the various cellular transplantation strategies that could be employed in the treatment of SCI. The success of such cellular approaches involving Schwann cells, olfactory ensheathing cells, peripheral nerve, embryonic CNS tissue and activated macrophage has been supported by a number of reports and has been detailed here. Many of these cell transplantation strategies have reached the clinical trial stages. Also, the evolving field of stem cell therapy has made it possible to contemplate the role of both embryonic stem cells and induced pluripotent stem cells to stimulate the differentiation of neurons when transplanted in SCI models. Moreover, the roles of tissue engineering techniques and synthetic biomaterials have also been explained with their beneficial and deleterious effects. Many of these cell-based therapeutic approaches have been able to cause only a little change in recovery and a combinatorial approach involving more than one strategy are now being tried out to successfully treat SCI and improve functional recovery.

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