Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking

Abstract

The striatum, the input structure of the basal ganglia, is a major site of learning and memory for goal-directed actions and habit formation. Spiny projection neurons of the striatum integrate cortical, thalamic, and nigral inputs to learn associations, with cortico-striatal synaptic plasticity as a learning mechanism. Signaling molecules implicated in synaptic plasticity are altered in alcohol withdrawal, which may contribute to overly strong learning and increased alcohol seeking and consumption. To understand how interactions among signaling molecules produce synaptic plasticity, we implemented a mechanistic model of signaling pathways activated by dopamine D1 receptors, acetylcholine receptors, and glutamate. We use our novel, computationally efficient simulator, NeuroRD, to simulate stochastic interactions both within and between dendritic spines. Dopamine release during theta burst and 20-Hz stimulation was extrapolated from fast-scan cyclic voltammetry data collected in mouse striatal slices. Our results show that the combined activity of several key plasticity molecules correctly predicts the occurrence of either LTP, LTD, or no plasticity for numerous experimental protocols. To investigate spatial interactions, we stimulate two spines, either adjacent or separated on a 20-μm dendritic segment. Our results show that molecules underlying LTP exhibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a spatially diffuse elevation. We also implement changes in NMDA receptors, adenylyl cyclase, and G protein signaling that have been measured following chronic alcohol treatment. Simulations under these conditions suggest that the molecular changes can predict changes in synaptic plasticity, thereby accounting for some aspects of alcohol use disorder.

A unified computational model for cortical post-synaptic plasticity

“…We started by using the model of [Jedrzejewska-Szmek et al, 2017] for GluR1 phosphorylation at sites S831 and S845, which are phosphorylated by protein kinase A (PKA) and Ca 2+ /calmodulin-dependent kinase II (CaMKII), respectively, as a basis for our unified model. We added the metabotropic glutamate receptor (mGluR) and muscarinic acetylcholine M1 receptor-dependent pathways leading to protein kinase C (PKC) activation from [Kim et al, 2013] and [Blackwell et al, 2018], respectively, and adopted the PKC-dependent endocytosis of GluR2 and reinsertion to the membrane from [Gallimore et al, 2018] as these pathways are critical for neocortical plasticity [Seol et al, 2007]. As we included molecular species from different models and as we omitted certain molecular species that affected the dynamics of the underlying species but were not imperative for the pathways we wanted to describe, calibration of the model reactions was necessary.…”

“…We adopted the simplified, mass-action law-based PKA activation model (reaction 59; Tab. 1) from [Williamson et al, 2009] (where it was called model "C") instead of the 2-stage, linearised cAMP-binding of PKA in [Jedrzejewska-Szmek et al, 2017] and [Blackwell et al, 2018]. We fitted the forward rate to data simulated with the original model ( Fig.…”

“…The full model along with the fitting and data-analysis algorithms (Python scripts) that were used in this study are publicly available in ModelDB at http://modeldb.yale.edu/260971 (password "plasticity" required during peer review). Iyengar, 1999, Jedrzejewska-Szmek et al, 2017], generic [Hayer and Bhalla, 2005], cerebellar Purkinje cells [Gallimore et al, 2018], striatal spiny projection neuron [Blackwell et al, 2018]…”

“…Hippocampal CA1 [Bhalla and Iyengar, 1999], striatal spiny projection neuron [Kim et al, 2013, Blackwell et al, 2018 cerebellar Purkinje cells [Hellgren Kotaleski et al, 2002, Gallimore et al, 2018…”

Papers arising from the 12th International Basal Ganglia Society Meeting. March 26th–30th 2017, Mérida, Yucatán, México

“…The increasing importance of the use of computational approaches to understand the nervous system, and EJN's inclusion of a computational section in the journal, is reflected by three original research papers in which computational approaches are used to understand complex cellular and network mechanisms that underlie basal ganglia function. A 'virtual robotic framework' is used to explore the role of D1 and D2 spiny neurons in action selection (Bahuguna et al, 2019), a 'neuro-computational' study is used to address the role of the subthalamic nucleus-external globus pallidus loop in exploratory decisions (Baladron et al, 2019) and a combined experimental and computational is used study to address the molecular mechanisms underlying synaptic plasticity in the striatum (Blackwell et al, 2019).…”