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Assessment of Dopaminergic Homeostasis in Mice by Use of High-performance Liquid Chromatography Analysis and Synaptosomal Dopamine Uptake
Published on: September 21, 2017
CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice
Noriaki Shimokawa1, Kaisa Haglund, Sabine M Hölter
1Institute of Biochemistry II and Cluster of Excellence Macromolecular Complexes, Goethe University, Frankfurt (Main), Germany.
Abstract:
Despite extensive investigations of Cbl-interacting protein of 85 kDa (CIN85) in receptor trafficking and cytoskeletal dynamics, little is known about its functions in vivo. Here, we report the study of a mouse deficient of the two CIN85 isoforms expressed in the central nervous system, exposing a function of CIN85 in dopamine receptor endocytosis. Mice lacking CIN85 exon 2 (CIN85(Deltaex2)) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85(Deltaex2) animals display abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum, an important centre for the coordination of animal behaviour. Importantly, CIN85 localizes to the post-synaptic compartment of striatal neurons in which it co-clusters with D2DRs. Moreover, it interacts with endocytic regulators such as dynamin and endophilins in the striatum. Absence of striatal CIN85 causes insufficient complex formation of endophilins with D2DRs in the striatum and ultimately decreased D2DR endocytosis in striatal neurons in response to dopamine stimulation. These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85(Deltaex2) mice.
Insights
Cbl-interacting protein of 85 kDa (CIN85) regulates dopamine receptor endocytosis in the brain. Mice lacking CIN85 exhibit hyperactivity due to impaired dopamine D2 receptor internalization in the striatum.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Cbl-interacting protein of 85 kDa (CIN85) is implicated in receptor trafficking and cytoskeletal dynamics.
- Its in vivo functions, particularly in the central nervous system, remain largely uncharacterized.
Purpose of the Study:
- To investigate the in vivo function of CIN85 in the central nervous system.
- To elucidate the role of CIN85 in dopamine receptor endocytosis and its impact on behavior.
Main Methods:
- Generation and analysis of mice deficient in CIN85 isoforms in the central nervous system (CIN85(Deltaex2)).
- Assessment of behavioral phenotypes, including physical activity and exploratory behavior.
- Measurement of dopamine and D2 dopamine receptor (D2DR) levels in the striatum.
- Immunolocalization studies to determine CIN85 localization and co-clustering with D2DRs.
- Investigation of CIN85 interactions with endocytic proteins like dynamin and endophilins.
- Analysis of D2DR endocytosis in response to dopamine stimulation.
Main Results:
- CIN85(Deltaex2) mice exhibit hyperactivity, increased physical activity, and exploratory behavior.
- These mice show elevated levels of dopamine and D2DRs in the striatum.
- CIN85 localizes to the post-synaptic compartment of striatal neurons and co-clusters with D2DRs.
- Absence of CIN85 leads to reduced endophilin-D2DR complex formation and impaired D2DR endocytosis in striatal neurons.
Conclusions:
- CIN85 plays a crucial role in regulating dopamine receptor function, specifically D2DR endocytosis, in the striatum.
- The findings provide a molecular basis for the observed hyperactive phenotype in CIN85-deficient mice.
- CIN85 is identified as a key regulator of dopamine signaling pathways in the central nervous system.
