Modeling Intracellular Signaling Underlying Striatal Function in Health and Disease

Abstract

Striatum, which is the input nucleus of the basal ganglia, integrates cortical and thalamic glutamatergic inputs with dopaminergic afferents from the substantia nigra pars compacta. The combination of dopamine and glutamate strongly modulates molecular and cellular properties of striatal neurons and the strength of corticostriatal synapses. These actions are performed via intracellular signaling networks, containing several intertwined feedback loops. Understanding the role of dopamine and other neuromodulators requires the development of quantitative dynamical models for describing the intracellular signaling, in order to provide precise unambiguous descriptions and quantitative predictions. Building such models requires integration of data from multiple data sources containing information regarding the molecular interactions, the strength of these interactions, and the subcellular localization of the molecules. Due to the uncertainty, variability, and sparseness of these data, parameter estimation techniques are critical for inferring or constraining the unknown parameters, and sensitivity analysis evaluates which parameters are most critical for a given observed macroscopic behavior. Here, we briefly review the modeling approaches and tools that have been used to investigate biochemical signaling in the striatum, along with some of the models built around striatum. We also suggest a future direction for the development of such models from the, now becoming abundant, high-throughput data.

Interactions between glutamate, dopamine, and the neuronal signature of response inhibition in the human striatum

“…In humans, there is evidence that striatal dopaminergic neurotransmission is related to impulsive personality characteristics [Buckholtz et al, 2010;de Wit et al, 2002] as well as to psychiatric disorders [Koob and Volkow, 2010;Swanson et al, 2007;Verbruggen and Logan, 2008]. In addition, the synaptic plasticity underlying reinforcement learning has been associated with neurochemical interactions of different neurotransmitters at the level of the striatum, with dopamine shown to play a key role [Cools and D'Esposito, 2011;Nair et al, 2014].…”

Neurotrophin‐3 restores synaptic plasticity in the striatum of a mouse model of Huntington's disease

“…A 3‐NP treatment has been shown to trigger LTP after HFS, and mitochondrial inhibition affects the membrane potential and increases the sensitivity of NMDA and AMPA receptors to glutamate, favoring the activity of PKA, which has been linked to the generation of striatal LTP . Nevertheless, this LTP is considered pathological; meanwhile, LTD is the physiological form of plasticity most frequently observed in the striatum.…”

“…16 A 3-NP treatment has been shown to trigger LTP after HFS, 25,26 and mitochondrial inhibition affects the membrane potential and increases the sensitivity of NMDA and AMPA receptors to glutamate, favoring the activity of PKA, which has been linked to the generation of striatal LTP. 27,28 Nevertheless, this LTP is considered pathological; meanwhile, LTD is the physiological form of plasticity most frequently observed in the striatum. Moreover, corticostriatal LTD involves endocannabinoid synthesis, which act as retrograde messengers at the corticostriatal synapses, activating CB1 receptors at the presynaptic neuron which, in turn, reduces neurotransmitter release and maintains LTD expression.…”

Uncertainty quantification, propagation and characterization by Bayesian analysis combined with global sensitivity analysis applied to dynamical intracellular pathway models

“…We have applied our approach to a previously constructed intracellular model that in a simplified way exemplifies a molecular mechanism important for the strengthening (long term potentiation, LTP) or weakening (long term depression, LTD) of neuronal synapses (Nair et al, 2014). The modification of synapses through the process of LTP or LTD is a complicated process including a number of kinases, phosphatases and scaffolding proteins (Woolfrey and Dell'Acqua, 2015).…”

“…The modification of synapses through the process of LTP or LTD is a complicated process including a number of kinases, phosphatases and scaffolding proteins (Woolfrey and Dell'Acqua, 2015). This process is, however, often assumed to be effectuated by the balance between a few important kinase and phosphatase enzymes, and in the model used in this study (Nair et al, 2014), this balance is due to the interaction between calcium (Ca), calmodulin (CaM), which contains four Ca-binding domains, protein phosphatase 2B (PP2B, also known as Calcineurin), Ca/CaM-dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1), as illustrated in Figure 3.…”