The second messenger cAMP is an important determinant of synaptic plasticity that is associated with enhanced neurotransmitter release. Long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell (PC) synapses depends on a Ca 21 -induced increase in presynaptic cAMP that is mediated by Ca 21 -sensitive adenylyl cyclases. However, the upstream signaling and the downstream targets of cAMP involved in these events remain poorly understood. It is unclear whether cAMP generated by b-adrenergic receptors (bARs) is required for PF-PC LTP, although noradrenergic varicosities are apposed in PF-PC contacts. Guanine nucleotide exchange proteins directly activated by cAMP [Epac proteins (Epac 1-2)] are alternative cAMP targets to protein kinase A (PKA) and Epac2 is abundant in the cerebellum. However, whether Epac proteins participate in PF-PC LTP is not known. Immunoelectron microscopy demonstrated that bARs are expressed in PF boutons. Moreover, activation of these receptors through their agonist isoproterenol potentiated synaptic transmission in cerebellar slices from mice of either sex, an effect that was insensitive to the PKA inhibitors (H-89, KT270) but that was blocked by the Epac inhibitor ESI 05. Interestingly, prior activation of these bARs occluded PF-PC LTP, while the b1AR antagonist metoprolol blocked PF-PC LTP, which was also absent in Epac2 2/2 mice. PF-PC LTP is associated with an increase in the size of the readily releasable pool (RRP) of synaptic vesicles, consistent with the isoproterenolinduced increase in vesicle docking in cerebellar slices. Thus, the bAR-mediated modulation of the release machinery and the subsequent increase in the size of the RRP contributes to PF-PC LTP.

Identification of BiP as a CB 1 receptor-interacting protein that fine-tunes cannabinoid signaling in the mouse brain

Aim: Due to the complex nature of Alzheimer's disease, there is a renewed search for multipotent, nonhepatotoxic tacrines. Results: This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl-2,4,6,7,8,9-hexahydropyrazolo[4′,3′:5,6]pyrano[2,3-b]quinolin-5-amines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Aβ1–40 aggregation induced by acetylcholinesterase. Conclusion: A new family of nonhepatotoxic showing selective acetylcholinesterase inhibition, permeable tacrine analogs have been discovered for the potential treatment of Alzheimer's disease.

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