The internal state of medium spiny neurons varies in response to different input signals
Miller, Gary W.
Voit, Eberhard O.
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Background Parkinson's disease, schizophrenia, Huntington's chorea and drug addiction are manifestations of malfunctioning neurons within the striatum region at the base of the human forebrain. A key component of these neurons is the protein DARPP-32, which receives and processes various types of dopamine and glutamate inputs and translates them into specific biochemical, cellular, physiological, and behavioral responses. DARPP-32's unique capacity of faithfully converting distinct neurotransmitter signals into appropriate responses is achieved through a complex phosphorylation-dephosphorylation system that evades intuition and predictability. Results To gain deeper insights into the functioning of the DARPP-32 signal transduction system, we developed a dynamic model that is robust and consistent with available clinical, pharmacological, and biological observations. Upon validation, the model was first used to explore how different input signal scenarios are processed by DARPP-32 and translated into distinct static and dynamic responses. Secondly, a comprehensive perturbation analysis identified the specific role of each component on the system's signal transduction ability. Conclusions Our study investigated the effects of various patterns of neurotransmission on signal integration and interpretation by DARPP-32 and showed that the DARPP-32 system has the capability of discerning surprisingly many neurotransmission scenarios. We also screened out potential mechanisms underlying this capability of the DARPP-32 system. This type of insight deepens our understanding of neuronal signal transduction in normal medium spiny neurons, sheds light on neurological disorders associated with the striatum, and might aid the search for intervention targets in neurological diseases and drug addiction.