Cellular and Synaptic Dysfunctions in Parkinson's Disease: Stepping out of the Striatum

Abstract

The basal ganglia (BG) are a collection of interconnected subcortical nuclei that participate in a great variety of functions, ranging from motor programming and execution to procedural learning, cognition, and emotions. This network is also the region primarily affected by the degeneration of midbrain dopaminergic neurons localized in the substantia nigra pars compacta (SNc). This degeneration causes cellular and synaptic dysfunctions in the BG network, which are responsible for the appearance of the motor symptoms of Parkinson's disease. Dopamine (DA) modulation and the consequences of its loss on the striatal microcircuit have been extensively studied, and because of the discrete nature of DA innervation of other BG nuclei, its action outside the striatum has been considered negligible. However, there is a growing body of evidence supporting functional extrastriatal DA modulation of both cellular excitability and synaptic transmission. In this review, the functional relevance of DA modulation outside the striatum in both normal and pathological conditions will be discussed.

Keywords: GABAergic transmission; Globus pallidus; dopamine; neuronal excitability; neuronal oscillations; pacemaking; substantia nigra; subthalamic nucleus.

Figure 1

Basal ganglia circuitry in rodents. (A) Schematic representing the main connections of the basal ganglia network in a sagittal section of the rodent brain. (B) Corresponding anatomical-functional diagram adapted from the Albin model of the basal ganglia [8]. Dopaminergic, GABAergic, and glutamatergic projections and nuclei are depicted in blue, purple and red, respectively. A: arkypallidal neuron; dSPN: direct-pathway spiny projection neuron; EPN: entopedoncular nucleus; GP: globus pallidus; iSPN: indirect-pathway spiny projection neuron; P: prototypic neuron; SNc: substantia nigra pars compacta; SNr: Substantia nigra pars reticulata; SIN: Striatal interneurons; STN: subthalamic nucleus.

Figure 2

Mechanisms underlying GABAergic synaptic alterations in the GP in experimental PD. (A) In DA-intact conditions, D2 receptors present on astrocyte membranes elevate intracellular calcium levels and promote glutamate gliotransmission. Glutamate activates group III mGluR (GluRIII), which reduces GABA release probability at striato-pallidal synapses. D2Rs also regulate GAT-3 activity by an unknown mechanism, preventing GABA spillover from GABAergic synapses and hence activation of extrasynaptic GABA_A receptors. (B) Under DA-depleted conditions, D2Rs are no longer activated, glutamate gliotransmission is reduced and mGluRIII-dependent reduction of GABA release is lost, leading to an increase in striato-pallidal transmission. The loss of D2R modulation of GAT-3 triggers a downregulation of the expression of the transporters, and the elevation of extracellular GABA concentrations leads to the activation of extrasynaptic GABA_A receptors, which favors tonic inhibition.

Figure 3

Cellular and synaptic alterations in the STN in experimental PD. (A) Schematic of the main post-synaptic and pre-synaptic molecular pathways involved in DA-dependent cellular excitability and synaptic plasticity. (B) Under DD conditions, post-synaptic and pre-synaptic DA modulation is lost. This triggers NMDA-dependent M1 cortex synapse pruning, NMDA-dependent and NO-dependent heterosynaptic LTP (synapse proliferation) at pallido-subthalamic GABAergic synapses and NMDA-dependent activation of K_ATP channels, which reduces STN autonomous pacemaking.

Figure 4

Cellular and synaptic alterations in the ESN in experimental PD. (A) Summary diagram of the main modifications in cellular excitability and synaptic transmission observed in the BG network under DA-depleted conditions. Black arrows indicate increase or decrease in synaptic transmission or intrinsic excitability (represented by black APs). Astr.: astrocyte involvement in GABAergic dysfunction in GP. GABAergic and glutamatergic projections and nuclei are depicted in blue and red, respectively. Loss of SNc DA neurons is represented by the dashed purple circle. (B) Schematic illustrating the modification in the balance between intrinsic neuronal excitability and synaptic strength in ESN as a function of the levels of DA.