BDNF-Regulated Modulation of Striatal Circuits and Implications for Parkinson's Disease and Dystonia

Abstract

Neurotrophins, particularly brain-derived neurotrophic factor (BDNF), act as key regulators of neuronal development, survival, and plasticity. BDNF is necessary for neuronal and functional maintenance in the striatum and the substantia nigra, both structures involved in the pathogenesis of Parkinson's Disease (PD). Depletion of BDNF leads to striatal degeneration and defects in the dendritic arborization of striatal neurons. Activation of tropomyosin receptor kinase B (TrkB) by BDNF is necessary for the induction of long-term potentiation (LTP), a form of synaptic plasticity, in the hippocampus and striatum. PD is characterized by the degeneration of nigrostriatal neurons and altered striatal plasticity has been implicated in the pathophysiology of PD motor symptoms, leading to imbalances in the basal ganglia motor pathways. Given its essential role in promoting neuronal survival and meditating synaptic plasticity in the motor system, BDNF might have an important impact on the pathophysiology of neurodegenerative diseases, such as PD. In this review, we focus on the role of BDNF in corticostriatal plasticity in movement disorders, including PD and dystonia. We discuss the mechanisms of how dopaminergic input modulates BDNF/TrkB signaling at corticostriatal synapses and the involvement of these mechanisms in neuronal function and synaptic plasticity. Evidence for alterations of BDNF and TrkB in PD patients and animal models are reviewed, and the potential of BDNF to act as a therapeutic agent is highlighted. Advancing our understanding of these mechanisms could pave the way toward innovative therapeutic strategies aiming at restoring neuroplasticity and enhancing motor function in these diseases.

Keywords: BDNF; PD; Parkinson’s disease; TrkB; brain-derived neurotrophic factor; dopamine; dystonia; neurological diseases; neuronal plasticity.

Figure 1

Motor cortex and substantia nigra contribute differently to striatal presynaptic brain-derived neurotrophic factor (BDNF). (A) High-resolution light microscopy of BDNF-containing terminals reveals high overlap with Vesicular glutamate transporter 1 (VGluT1) staining (magenta arrows), whereas overlap with tyrosine hydroxylase (TH)-immunoreactive structures was less frequently observed (white arrows). Scale bar: 1.5 µm. (B) Quantification of VGluT1-positive synapses (left, blue) and VGluT1-BDNF double-positive synapses (left, magenta). Also the numbers of TH-positive synapses were quantified (right, blue), as well as TH-BDNF double-positive synapses (right, magenta). Figure modified from Andreska et al. (2020) [18] (licensed under CC BY 4.0).

Figure 2

Dorsal striatal BDNF is delivered from Layer II/III and V of the motor cortex. (A) BDNF-expressing striatal afferents have their origin in the motor cortex (left). Retrograde tracing from the dorsal striatum identifies neurons in Layer II/III (Cux1-positive) and Layer V (Ctip-2-positive) of the motor cortex (right). Scale bar: 150 µm. (B) BDNF-expressing neurons in the motor cortex are also positive for the retrograde tracer injected into the dorsal striatum (white arrows). Not all BDNF-positive neurons were positive for the retrograde tracer (yellow arrow). Scale bar: 50 µm. Figure modified from Andreska et al. (2020) [18] (licensed under CC BY 4.0).

Figure 3

The subcellular distribution of tropomyosin receptor kinase B (TrkB) is altered in patients with Parkinson’s Disease (PD) and rodent models of PD. (A) In the striatum of PD patients, Trk receptors accumulate in perinuclear clusters (arrow), whereas in healthy subjects, Trk appears evenly distributed in the soma and on the cell surface of striatal neurons. Scale bar: 10 µm. (B) Striatal intracellular clusters of TrkB are readily observed after 6-Hydroxydopamine (6-OHDA) injection. These clusters can be partially prevented with L-DOPA treatment (top). TrkB trafficking to the cell surface is dependent on vesicular exocytotic transport from the endoplasmic reticulum (ER). In models of PD, TrkB-containing vesicles associate with the cargo receptor SORCS-2 but cannot be transported to the cell surface. As a consequence, TrkB forms the observed aggregates, which fail to be cleared via the lysosomal degradation pathway (bottom). Figure modified from Andreska et al. (2023) [170] (licensed under CC BY 4.0).

Figure 4

Dopaminergic modulation of the BDNF/TrkB signaling pathways in PD and dystonia. Spiny projection neurons from the direct and indirect pathways in the striatum express D1 and D2 receptors, respectively. D1 receptors recruit Gα_s/olf proteins and activate adenylyl cyclase. Increased production of cyclic adenosine monophosphate (cAMP) promotes the translocation of TrkB receptors from intracellular compartments to the cell surface, thus increasing the sensitivity for BDNF and, in turn, increasing the TrkB phosphorylation levels (upwards arrow). Inversely, D2 receptors recruit Gα_i/o/z proteins for inhibition of adenylyl cyclase and decreased cAMP production. This inhibits TrkB translocation to the cell surface and decreases its phosphorylation (downwards arrow). In PD, dopaminergic denervation (red slash) causes aberrant TrkB cellular distribution. In dystonia, reduced activation of D2 receptors and enhanced activation of D1 receptors could cause hyperactivation of BDNF/TrkB signaling (question marks indicate hypothetical mechanisms).