The internal state of medium spiny neurons varies in response to different input signals

Abstract

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.

Figure 1

Signal integration and interpretation by the DARPP-32 system in dendrites of medium spiny neurons in the striatum. The membrane of spiny neurons (solid curved line) contains receptors for the neurotransmitters dopamine and glutamate, which had been released by other neurons into the synaptic cleft. Diamonds show molecular binding, while arrows with plus signs designate activation or enzymatic reactions and dash-dotted lines with bars indicate inhibition. Shaded boxes in green color represent phosphorylated forms of DARPP-32, with labels indicating the specific phosphorylated site, and arrows showing possible transitions between the different phosphorylation states. Open block arrows indicate possible multiple-site phosphorylation. Please refer to the Figure 2 for a detailed map of all possible transitions between different phosphorylation forms. Abbreviations are: dopamine receptor of D₁ subtype (D₁), dopamine receptor of D₂ subtype (D₂), G protein and subunits (G_αβγ, G_α), adenylate cyclase (AC5), cyclic AMP (cAMP), phosphodiesterases (PDE1, PDE4), protein kinase A (PKA, PKAc), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), protein phosphatase 2B (PP2Bi, PP2B), protein phosphatase-1 (PP1), protein phosphatase 2A (PP2A), cyclin-dependent kinase 5 (CDK5), casein kinase 2 (CK2), casein kinase 1 (CK1), protein phosphatase 2C (PP2C), dopamine- and cAMP-regulated phosphoprotein with 32 kDa molecular weight (DARPP-32). Phosphorylation of DARPP-32 is indicated by the corresponding amino acid and location, such as DARPP-32Thr³⁴. See Figure 2 for multiple-site phosphorylation.

Figure 2

Phosphorylation states of DARPP-32. Differently shaded boxes show singly, doubly and triply phosphorylated states of DARPP-32, and labels indicate phosphorylation positions. Arrows indicate transitions between different phosphorylation forms through enzymatic reactions. Dash-dotted lines with bars represent inhibition. Abbreviations are: protein phosphatase-1 (PP1), protein kinase A (PKAc), dopamine- and cAMP-regulated phosphoprotein with 32 kDa molecular weight (DARPP-32). Different phosphorylation states of DARPP-32 are indicated by the corresponding amino acid(s) and location(s). For instance, (Thr³⁴-Ser¹⁰²) refers to DARPP-32 phosphorylated simultaneously at positions 34 and 102.

Figure 3

Schematic representation of input signal patterns. The left panel illustrates one-shot scenarios of input signals, while the right panel shows repetitive input signals. Solid lines represent transient signals, while dashed lines show sustained input signals.

Figure 4

Typical responses of the DARPP-32 system to dopamine and glutamate (Ca²⁺ influx) signals. Panel A shows a typical response of the system to a sole dopamine signal, while panel B exhibits a representative response of the system to a sole glutamate (Ca²⁺ influx) signal. Panel C shows a common response of the system to a combination of dopamine and Ca²⁺ signals.

Figure 5

Different responses of the DARPP-32 system to a transient or a sustained signal. Input signals are repetitive, high-amplitude Ca²⁺ influxes (corresponding to glutamate stimulation) with a time scale of milliseconds. Blue lines: Responses to a transient signal; red lines: Responses to a sustained signal.

Figure 6

Different responses of the DARPP-32 system to a one-shot or a repetitive signal. Input signals are combinations of a dopamine signal and Ca²⁺ influx. They have low amplitude and a sustained shape with a time scale of seconds. Blue lines: Responses to a one-shot signal; red lines: Responses to a repetitive signal.

Figure 7

Different dynamics of the DARPP-32 system in response to a high- or a low- amplitude signal. Input signals are repetitive, sustained Ca²⁺ influxes with a time scale of seconds. Blue lines: Responses to a high amplitude signal; red lines: Responses to a low amplitude signal.

Figure 8

Different steady states of the DARPP-32 system in response to a high- or a low- amplitude signal. Input signals are combinations of dopamine stimulation and Ca²⁺ influx. They are repetitive, transient with a time scale of milliseconds. Blue lines: Responses to a high amplitude signal; red lines: Responses to a low amplitude signal.