Event Abstract Back to Event Electrophysiological and molecular mechanisms of synaptic plasticity in the striatum: multi-scale simulation of molecule and cell Takashi Nakano1*, Junichiro Yoshimoto1, Jeff Wickens1 and Kenji Doya1 1 Okinawa Institute of Science and Technology, Japan The striatum receives glutamatergic input from the cortex and dopaminergic input from the substantia nigra. These inputs, acting together, induce long-term change of corticostriatal synaptic strength, which plays a critical role in learning from reward. Although a number of laboratories have investigated corticostriatal synaptic plasticity, contradictory results and properties have been reported and it is difficult to elucidate the dependence of corticostriatal synaptic plasticity on dopamine, as well as the timing of presynaptic inputs and spike output only by experimentation. To clarify electrophysiological and molecular mechanisms behind the plasticity of striatal synapses, we have constructed models of medium spiny neurons at cellular and molecular levels: an electric compartmental model with a realistic cell morphology (Nakano et al., 2009), and a molecular signaling pathway model (Nakano et al., 2010). These two models operate at different time scales and spatial scales. There are interactions between the two levels. For example, the activation of a postsynaptic signaling cascade is affected by the whole cell electric activity. This makes it difficult to understand the mechanisms only by single models and we need to construct a multi-scale model. In this study, we connected the two models serially, as shown by the solid line in the Figure. First, we constructed an electric compartment model with realistic morphology obtained from our experiments, to investigate the glutamate and dopamine timing effects on the calcium responses and its electrophysiological mechanisms. The parameters were adjusted based on electrophysiological data. The model prediction was that the calcium response is maximal when the glutamate input leads the postsynaptic spike, and that this spike-timing-dependent calcium response was facilitated when the dopamine preceded the glutamate. This suggests the possibility that dopamine timing regulates corticostriatal spike-timing dependent synaptic plasticity (STDP) through its effect on the calcium response. Second, we constructed a signaling pathway model of synaptic spines expressing D1-type dopamine receptors and examined the mechanisms of dopamine- and calcium-dependent plasticity. The model predicted the synaptic changes induced by dopamine and calcium inputs. The positive feedback loop including dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) shows bistability and its activation by dopamine input induces dopamine dependent long-term potentiation (LTP). Calcium input alone also caused synaptic efficacy change through several pathways as CaMKII and PP1. The model predicted that the timing of calcium and dopamine inputs has only minor effect on the synaptic change. Finally, by connecting the two models, we predicted synaptic efficacy change induced by a variety of strength and timing of glutamate and dopamine inputs. Although dopamine modulation of channels and receptors is mediated through signaling cascades (blue dashed line in the figure), here, for simplicity, we used output of the electric compartment model as a calcium input for the signaling cascade model. To connect two models, the output data from the electric compartment model was fed as the input to the cascade model. The model reproduced some types of synaptic plasticity which were reported by experiments: 1) High-frequency stimulation (HFS) induces calcium influx, which leads to long-term depression (LTD). 2) HFS in up-state induces a strong calcium response and LTP. 3) LTP is also induced by HFS with dopamine input. 4) STDP is reproduced when NMDA receptors currents are enhanced. The major new findings from the combined system were that the time integral of the calcium response is a good indicator of the synaptic plasticity and that the major effect of the dopamine timing is through its modulation of the calcium response rather than through the temporal response of the molecular signaling cascade.
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Open Access
Jun 1, 2010
Ming-Chia Lee + 2
