4.6 Article

Dopaminergic Input Regulates the Sensitivity of Indirect Pathway Striatal Spiny Neurons to Brain-Derived Neurotrophic Factor

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BIOLOGY-BASEL
卷 12, 期 10, 页码 -

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MDPI
DOI: 10.3390/biology12101360

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BDNF; TrkB; cortico-striatal synapse; basal ganglia; indirect pathway; DRD2; iSPNs; synaptic plasticity; GPCR; cholinergic interneurons; Pitx3

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Motor dysfunction in Parkinson's disease is linked to the depletion of dopamine and altered synaptic plasticity in striatal neurons. Stimulation of dopamine receptor D1 enhances synaptic plasticity in direct pathway spiny projection neurons, while stimulation of dopamine receptor D2 inhibits synaptic plasticity in indirect pathway spiny projection neurons. This study demonstrates the role of tropomyosin receptor kinase B (TrkB) and brain-derived neurotrophic factor (BDNF) in regulating synaptic plasticity at corticostriatal synapses. Dysregulated BDNF/TrkB signaling may contribute to the pathophysiology of both direct and indirect pathway striatal projection neurons in Parkinson's disease.
Simple Summary Motor dysfunction is among the main symptoms of Parkinson's disease (PD). This is closely linked to the loss of the neurotransmitter dopamine (DA) in the midbrain and in the striatum. Additionally, the ability of striatal neurons to undergo adaptive cellular alterations and synaptic plasticity is impaired. Dopamine receptor D1 (DRD1) stimulation is needed for the establishment of long-term potentiation (LTP) at synapses of striatal spiny projection neurons (SPNs), which leads to enhanced neurotransmission. In contrast, dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in SPNs, which leads to the opposite effect. The tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal neurons synapses. There are two populations of striatal SPNs, with different projection targets in the brain. DRD1 is expressed in direct pathway spiny projection neurons (dSPNs) and its activation enhances TrkB sensitivity for BDNF by increasing the levels of TrkB at the cell surface. In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs in Pitx3-/- mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD.Abstract Motor dysfunction in Parkinson's disease (PD) is closely linked to the dopaminergic depletion of striatal neurons and altered synaptic plasticity at corticostriatal synapses. Dopamine receptor D1 (DRD1) stimulation is a crucial step in the formation of long-term potentiation (LTP), whereas dopamine receptor D2 (DRD2) stimulation is needed for the formation of long-term depression (LTD) in striatal spiny projection neurons (SPNs). Tropomyosin receptor kinase B (TrkB) and its ligand brain-derived neurotrophic factor (BDNF) are centrally involved in plasticity regulation at the corticostriatal synapses. DRD1 activation enhances TrkB's sensitivity for BDNF in direct pathway spiny projection neurons (dSPNs). In this study, we showed that the activation of DRD2 in cultured striatal indirect pathway spiny projection neurons (iSPNs) and cholinergic interneurons causes the retraction of TrkB from the plasma membrane. This provides an explanation for the opposing synaptic plasticity changes observed upon DRD1 or DRD2 stimulation. In addition, TrkB was found within intracellular structures in dSPNs and iSPNs from Pitx3-/- mice, a genetic model of PD with early onset dopaminergic depletion in the dorsolateral striatum (DLS). This dysregulated BDNF/TrkB signaling might contribute to the pathophysiology of direct and indirect pathway striatal projection neurons in PD.

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