DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons

Thomas Andreska; Patrick Lüningschrör; Daniel Wolf; Rhonda L McFleder; Maurilyn Ayon-Olivas; Marta Rattka; Christine Drechsler; Veronika Perschin; Robert Blum; Sarah Aufmkolk; Noelia Granado; Rosario Moratalla; Markus Sauer; Camelia Monoranu; Jens Volkmann; Chi Wang Ip; Christian Stigloher; Michael Sendtner

doi:10.1016/j.celrep.2023.112575

DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons

Cell Rep. 2023 Jun 27;42(6):112575. doi: 10.1016/j.celrep.2023.112575. Epub 2023 May 29.

Authors

Thomas Andreska¹, Patrick Lüningschrör¹, Daniel Wolf¹, Rhonda L McFleder², Maurilyn Ayon-Olivas¹, Marta Rattka², Christine Drechsler³, Veronika Perschin⁴, Robert Blum², Sarah Aufmkolk⁵, Noelia Granado⁶, Rosario Moratalla⁶, Markus Sauer⁷, Camelia Monoranu⁸, Jens Volkmann², Chi Wang Ip², Christian Stigloher⁴, Michael Sendtner⁹

Affiliations

¹ Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany.
² Department of Neurology, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.
³ Department of Microbiology, Biocenter, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany.
⁴ Imaging Core Facility of the Biocenter, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany.
⁵ Department of Biotechnology and Biophysics, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁶ Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, 28002 Madrid, Spain.
⁷ Department of Biotechnology and Biophysics, Julius-Maximilians-University Wuerzburg, 97074 Wuerzburg, Germany.
⁸ Department for Neuropathology, Julius-Maximilians-University Wuerzburg, 97080 Wuerzburg, Germany.
⁹ Institute of Clinical Neurobiology, University Hospital Wuerzburg, 97078 Wuerzburg, Germany. Electronic address: sendtner_m@ukw.de.

PMID: 37252844
DOI: 10.1016/j.celrep.2023.112575

Abstract

Disturbed motor control is a hallmark of Parkinson's disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD.

Keywords: BDNF; CP: Neuroscience; DRD1; GPCR; TrkB; basal ganglia; cortico-striatal synapse; dSPN; direct pathway; motor learning; synaptic plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain-Derived Neurotrophic Factor / metabolism
Corpus Striatum / metabolism
Dopamine / metabolism
Humans
Medium Spiny Neurons
Oxidopamine
Parkinson Disease* / metabolism
Rats
Receptor, trkB / metabolism
Receptors, Dopamine D1* / metabolism

Substances

Brain-Derived Neurotrophic Factor
Dopamine
DRD1 protein, human
Oxidopamine
Receptor, trkB
Receptors, Dopamine D1