Co-induction of LTP and LTD and its regulation by protein kinases and phosphatases.

Division of Basic Biomedical Science, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA.

Journal of neurophysiology 2010 May

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The cellular properties of long-term potentiation (LTP) following pairing of pre- and postsynaptic activity were examined at a known glutamatergic synapse in the leech, specifically between the pressure (P) mechanosensory and anterior pagoda (AP) neurons. Stimulation of the presynaptic P cell (25 Hz) concurrent with a 2 nA depolarization of the postsynaptic AP cell significantly potentiated the P-to-AP excitatory postsynaptic potential (EPSP) in an N-methyl-d-aspartate receptor (NMDAR)-dependent manner based on inhibitory effects of the NMDAR antagonist MK801 and inhibition of the NMDAR glycine binding site by 7-chlorokynurenic acid. LTP was blocked by injection of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) into the postsynaptic (AP) cell, indicating a requirement for postsynaptic elevation of intracellular Ca(2+). Autocamtide-2-related inhibitory peptide (AIP), a specific inhibitor of Ca(2+)/calmodulin-dependent kinase II (CaMKII), and Rp-cAMP, an inhibitor of protein kinase A (PKA), also blocked pairing-induced potentiation, indicating a requirement for activation of CaMKII and PKA. Interestingly, application of AIP during pairing resulted in significantly depressed synaptic transmission. Co-application of AIP with the protein phosphatase inhibitor okadaic acid restored synaptic transmission to baseline levels, suggesting an interaction between CaMKII and protein phosphatases during induction of activity-dependent synaptic plasticity. When postsynaptic activity preceded presynaptic activity, NMDAR-dependent long-term depression (LTD) was observed that was blocked by okadaic acid. Postsynaptic injection of botulinum toxin blocked P-to-AP potentiation while postsynaptic injection of pep2-SVKI, an inhibitor of AMPA receptor endocytosis, inhibited LTD, supporting the hypothesis that glutamate receptor trafficking contributes to both LTP and LTD at the P-to-AP synapse in the leech.

Citation

Kathryn B Grey, Brian D Burrell. Co-induction of LTP and LTD and its regulation by protein kinases and phosphatases. Journal of neurophysiology. 2010 May;103(5):2737-46