kt-5720 and astressin

The climbing fibre (CF) input controls cerebellar Purkinje cell (PC) activity as well as synaptic plasticity at parallel fibre (PF)-PC synapses. Under high activity conditions, CFs release not only glutamate, but also the neuropeptide corticotropin-releasing factor (CRF). Brief periods of such high CF activity can lead to the induction of long-term depression (LTD) at CF-PC synapses. Thus, we have examined for the first time the role of CRF in regulating excitatory postsynaptic currents (EPSCs) and long-term plasticity at this synapse. Exogenous application of CRF alone transiently mimicked three aspects of CF-LTD, causing reductions in the CF-evoked excitatory postsynaptic current, complex spike second component and complex spike afterhyperpolarization. The complex spike first component is unaffected by CF-LTD induction and was similarly unaffected by CRF. Application of a CRF receptor antagonist reduced the expression amplitude and induction probability of CF-LTD monitored at the EPSC level. Collectively, these results suggest that under particular sensorimotor conditions, co-release of CRF from climbing fibres could down-regulate excitatory transmission and facilitate LTD induction at CF-PC synapses. Inhibition of either protein kinase C (PKC) or protein kinase A (PKA) attenuated the effects of CRF upon CF-EPSCs. We have previously shown that CF-LTD induction is PKC-dependent, and here demonstrate PKA-dependence as well. These results suggest that both the acute effects of CRF on CF-EPSCs as well as the facilitating effect of CRF on CF-LTD induction can be explained by a CRF-mediated recruitment of PKC and PKA.

Topics: Animals; Animals, Newborn; Carbazoles; Cerebellum; Corticotropin-Releasing Hormone; Drug Interactions; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; In Vitro Techniques; Indoles; Neuronal Plasticity; Peptide Fragments; Purkinje Cells; Pyrroles; Rats; Rats, Sprague-Dawley; Synapses; Synaptic Transmission

The molecular mechanisms underlying long-term potentiation (LTP) in the CA1 region of the hippocampus are known to vary with developmental age. The physiological factors regulating this developmental change, however, have not yet been elucidated. Here we show that mild neonatal isolation accelerates the developmental switch in the signalling cascades for hippocampal CA1 LTP induction from a cyclic AMP-dependent protein kinase (PKA)- to a Ca2(+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pattern via the activation of the corticotrophin-releasing factor (CRF) system. Furthermore, this action appears to be mediated through an increased transcription of the alpha isoform of the CaMKII (CaMKIIalpha) gene. We also demonstrate that application of CRF to cultured hippocampal neurones significantly increases the expression of CaMKIIalpha, which is blocked by the non-specific CRF receptor antagonist astressin, the specific CRF receptor 1 antagonist NBI 27911, and the PKA inhibitor KT5720, but not by the CRF receptor 2 antagonist K 41498, or the protein kinase C inhibitor, bisindolylmaleimide I. CRF signalling also mediates the normal maturation of LTP. These results suggest a novel role for CRF in regulating early developmental events in the hippocampus, and indicate that, although maternal deprivation is stressful for the neonate, appropriate neonatal isolation can serve to promote an endocrine state that fosters the rate of maturation of the signalling cascades underlying the induction of LTP in the developing hippocampus.

Topics: Age Factors; Animals; Animals, Newborn; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Carbazoles; Cells, Cultured; Corticotropin-Releasing Hormone; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Hippocampus; Indoles; Long-Term Potentiation; Maternal Deprivation; Neurons; Peptide Fragments; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; RNA, Messenger; Signal Transduction; Synaptic Transmission