Modulation of hippocampal calcium signalling and plasticity by serine/threonine protein phosphatases.
Kinases and phosphatases act antagonistically to maintain physiological phosphorylation/dephosphorylation at numerous intracellular sites critical for neuronal signalling. In this study, it was found that inhibition of serine/threonine phosphatases by exposure of hippocampal slices to okadaic acid (OA) or cantharidin (CA; 100 nmol/L) for 2 h resulted in reduced basal synaptic transmission and blocked the induction of synaptic plasticity in the form of long-term potentiation as determined by electrophysiological analysis. Fura-2 Ca(2+) imaging revealed a bidirectional modulation of N-methyl-D-aspartate (NMDA) -mediated Ca(2+) responses and reduced KCl-mediated Ca(2+) responses in neonatal cultured hippocampal neurons after phosphatase inhibition. While OA inhibited NMDA-induced Ca(2+) influx both acutely and after incubation, CA-enhanced receptor-mediated Ca(2+) signalling at low concentrations (1 nmol/L) but reduced NMDA and KCl-mediated Ca(2+) responses at higher concentrations (100 nmol/L). Changes in Ca(2+) signalling were accompanied by increased phosphorylation of cytoskeletal proteins tau and neurofilament and the NMDA receptor subunit NR1 in selective treatments. Incubation with OA (100 nmol/L) also led to the disruption of the microtubule network. This study highlights novel signalling effects of prolonged inhibition of protein phosphatases and suggests reduced post-synaptic signalling as a major mechanism for basal synaptic transmission and long-term potentiation impairments.
Koss
David J
DJ
School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK.
Hindley
Kathleen P
KP
Riedel
Gernot
G
Platt
Bettina
B
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002193:Cantharidin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D016875:tau Proteins; D019319:Okadaic Acid; D016202:N-Methylaspartate; D011189:Potassium Chloride; D010749:Phosphoprotein Phosphatases; D002193:Cantharidin; D002118:Calcium