Regulation of synaptic facilitation by postsynaptic Ca2+/CaM pathways in hippocampal CA1 neurons.
1. Current- and voltage-clamp recordings with simultaneous field potential recordings were used to study the cellular and molecular mechanisms that contribute to synaptic facilitation at CA1 synapses in rat hippocampal slices. Microelectrodes used for intracellular recordings were also used to inject modulators of intracellular signal pathways into postsynaptic CA1 neurons. 2. Paired-pulse stimulation at constant stimulus intensity was used to analyze the relationship between the first evoked response (R1) and the absolute value of paired-pulse synaptic facilitation (R2-R1). The magnitudes of these two measures were inversely correlated. Compared with synapses that control motor functions, the synapses of CA1 pyramidal neurons did not exhibit accumulative synaptic facilitation during repetitive stimulation, which is often believed to be mediated by presynaptic residual Ca2+. 3. During studies on the cellular location of mechanisms contributing to synaptic facilitation, we observed that postsynaptic injections of 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetra-acetic acid or [Ala286]CaMKII281-302 [a Ca2+/calmodulin-dependent protein kinase II (CaM-KII) inhibitor peptide] prevented the decreases in paired-pulse facilitation (PPF) and synaptic potentiation induced by elevating extracellular Ca2+. These results show that raising extracellular Ca2+ enhances synaptic transmission in part by activating postsynaptic Ca2+ signal pathways. 4. The injection of Ca2+/calmodulin (CaM) into postsynaptic neurons significantly decreased PPF in 50 of 57 experiments while inducing synaptic potentiation; the Ca2+/CaM-induced synaptic potentiation and PPF attenuation occluded subsequent high Ca(2+)-induced enhancements of synaptic transmission. The changes in PPF induced by postsynaptic injections of Ca2+/CaM were inversely correlated with R1 potentiation. 5. The decreases in PPF induced by postsynaptic Ca2+/CaM injections were prevented by coinjecting pseudosubstrate inhibitors or substrate peptides of CaM-KII and protein kinase C (PKC), and were reversed by subsequent application of cyclothiazide (a blocker of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor desensitization). 6. Our results reveal that postsynaptic Ca2+/CaM signal pathways can modulate synaptic facilitation in the CNS, and the activities of CaM-KII and PKC are involved in this modulation. The physiological significance of such modulation is that synaptic strength could be potentiated by activation of Ca2+/CaM pathways during integration of important sensory input (e.g., learning and memory), whereas decreases in synaptic facilitation may protect synaptic transmission during extreme stimulation so that neuronal signal mechanisms can more accurately code neural information.
Wang
J H
JH
Department of Neurobiology and Anatomy, University of Texas Medical School Houston 77030, USA.
Kelly
P T
PT
D000818:Animals; D002118:Calcium / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000502:physiology*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008845:Microinjections; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
D002147:Calmodulin; D004791:Enzyme Inhibitors; D004533:Egtazic Acid; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium