INTRODUCTION: Long-term synaptic plasticity (LTSP) is a complex phenomenon. Experiments utilizing different LTSP-inducing paradigms have demonstrated activation of multiple signaling pathways and uncovered differences in neuromodulatory dependence. For example, dopaminergic (D1R) activation can retroactively convert spike-timing dependent depression to potentiation. On the other hand, inhibition of beta‑adrenergic (βAR) and not D1R activation can block induction of late, protein-synthesis dependent phase of LTSP (L‑LTSP) evoked by rate‑dependent paradigms (RTP). This is confusing because activation of both D1R and βAR increase cAMP activity and activate its targets. AIM(S): Understand the impact of differences in temporal patterns of synaptic and neuronal activity on activation of signaling pathways and signal transduction. METHOD(S): We used two detailed, multi-compartmental, morphologically realistic models of the CA1 neuron: 1) a conductance‑based neuron model, and 2) a stochastic reaction‑diffusion model of calcium‑, βAR‑, and D1R‑activated signaling pathways underlying LTSP. The latter model allows for simulating, monitoring, and controlling molecular concentrations in a dendritic spine and a dendritic segment. RESULTS: Modulation of dendritic potassium ion channels (e.g., SK, Kv1.1) by protein kinase A (PKA) may explain the observed differences in neuromodulatory requirements of STDP and RTP. To predict whether paradigms eliciting spike-timing dependent plasticity will induce L-LTSP, we studied the activity of key molecules implicated in plasticity, such as calcium calmodulin-dependent protein kinase II (CaMKII) and PKA. In the spine, we studied molecular species that are involved in actin cytoskeleton remodelling, and in the dendrite – particularly those that play a role in protein synthesis. CONCLUSIONS: These preliminary results suggest that molecular activity micro-spatial scales can predict the induction of L‑LTSP.
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