Thinking Outside the Box (and Arrow): Current Themes in Striatal Dysfunction in Movement Disorders

Abstract

The basal ganglia are an intricately connected assembly of subcortical nuclei, forming the core of an adaptive network connecting cortical and thalamic circuits. For nearly three decades, researchers and medical practitioners have conceptualized how the basal ganglia circuit works, and how its pathology underlies motor disorders such as Parkinson's and Huntington's diseases, using what is often referred to as the "box-and-arrow model": a circuit diagram showing the broad strokes of basal ganglia connectivity and the pathological increases and decreases in the weights of specific connections that occur in disease. While this model still has great utility and has led to groundbreaking strategies to treat motor disorders, our evolving knowledge of basal ganglia function has made it clear that this classic model has several shortcomings that severely limit its predictive and descriptive abilities. In this review, we will focus on the striatum, the main input nucleus of the basal ganglia. We describe recent advances in our understanding of the rich microcircuitry and plastic capabilities of the striatum, factors not captured by the original box-and-arrow model, and provide examples of how such advances inform our current understanding of the circuit pathologies underlying motor disorders.

Keywords: direct and indirect pathway; dopamine acetylcholine balance; neurodegenerative diseases; striatal interneurons; striatal projection neurons; synaptic plasticity; synchronous oscillations.

Figure 1.

(A) The original Box-and-Arrow model, reformatted. (B) An updated model includes the thalamostriatal, subthalamopallidal (STN → GPe), pallidostriatal and pallidocortical pathways (Saunders and others 2015) as well as striatal interneurons and collaterals. d/iSPNs, direct/indirect pathway spiny projection neurons; GPe/i, external/internal segments of the globus pallidus; SNc/r, substantia nigra pars compacta/reticulata; SC, superior colliculus; INs, striatal interneurons; D₁R/D₂R, dopamine D₁/D₂ receptors; FC, frontal cortex; ACh, acetylcholine.

Figure 2.

Parkinson’s disease (PD). Loss of dopamine weakens the direct pathway and strengthens the indirect pathway, leading to elevated inhibitory outflow from the basal ganglia (BG).

Figure 3.

Huntington’s disease (HD). Preferential loss of indirect pathway spiny projection neurons (iSPNs) leads to relative overactivation of the direct pathway, leading to decreased inhibitory outflow from the basal ganglia (BG).

Box 1 Figure.

Cortico-basal ganglia oscillations in the box-and-arrow model of Parkinson’s disease (PD). (A) Box-and-arrow diagram for PD, including the recurrent connections between the subthalamic nucleus (STN) and external segment of the globus pallidus (GPe), which are considered a possible driver of parkinsonian oscillations (the weakened cortex-STN link (Chu and others 2017) is omitted). (B) Same network after subsuming the thalamus into the cortex (both are excitatory) and after subsuming the indirect pathway into an effective excitatory direct pathway that is enhanced in PD. (C) Further collapsing the direct and indirect pathway and the striatum as a whole into a delayed excitatory cortex-GPi (GPi is the internal segment of the globus pallidus) link whose gain is elevated relative to the normal condition. (D) Increasing the gain in a simplified basal ganglia (BG) network (at t = 250 ms) can give rise to oscillations due to synaptic delays along the entire cortico-BG circuit.

Box 2 Figure.

Striatal microcircuitry. (A) rendition of the striatum in original box-and-arrow model (with dSPN and iSPN collapsed to a single SPN), which includes only cortical and dopaminergic afferent inputs. (B) Cholinergic interneurons (CINs) are reciprocally (Chuhma and others 2011) connected to SPNs and terminate on dopamine axons. (C) GABAergic interneurons with their known connections to SPNs, reciprocal connections, and their cortical and dopaminergic inputs. (D) A current snapshot of known striatal circuitry, including afferent inputs from the GPe and the thalamic parafascicular nucleus (PfN). Highlights: (1) CINs and PLTSIs are tonically active autonomous pacemaker neurons; (2) CINs and TH interneurons are the only interneurons known to receive direct SPN input; (3) CINs and FSIs do not communicate with each other; 4) cortical and thalamic feedforward inhibition is mediated by a different subset of GABAergic interneurons. Abbreviations: see text.

Box 3 Figure.

Synaptic plasticity. Pre- and postsynaptic signaling cascades responsible for long-term potentiation/depression (LTP/LTD). Abbreviations: MEK-ERK, mitogen-activated protein kinase kinase (MEK)–extracellular signal-regulated kinase (ERK); AKT, protein kinase B; PLC, phospholipase C; PI3K, phosphoinositide 3-kinase; CICR, calcium-induced calcium release; PLD, phospholipase D; eCB, endocannabinoid; µ/δOR, µ/δ opioid receptor; 5-HT1bR, 5-HT type 1b receptor; other abbreviations as in text.

Figure 4.

Current models of striatal circuit pathology in PD and HD. Diagrams focus on functional and anatomical microcircuit alterations; simplified and non-exhaustive due to space constraints. A. Circuit pathologies in PD. B. Circuit pathologies in early symptomatic HD, pre-SPN death. The diagrams highlight unique and complex constellations of striatal circuit alterations (not just elevated direct and indirect pathways) that sum to yield disease symptomatology. Loci of circuit alterations are highlighted in red/green and labeled. Abbreviations: see text.