Abstract
Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. However, the precise mechanisms underlying the trafficking of neurotrophin receptors to synapses remain elusive. Here, we demonstrate that a brain-enriched sorting nexin, ARHGAP33, is a new type of regulator for the intracellular trafficking of TrkB, a high-affinity receptor for brain-derived neurotrophic factor. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. Mechanistically, ARHGAP33 interacts with SORT1 to cooperatively regulate TrkB trafficking. Human ARHGAP33 is associated with brain phenotypes and reduced SORT1 expression is found in patients with schizophrenia. We propose that ARHGAP33/SORT1-mediated TrkB trafficking is essential for synapse development and that the dysfunction of this mechanism may be a new molecular pathology of neuropsychiatric disorders.
Highlights
Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits
We argue that ARHGAP33/SORT1-mediated TrkB trafficking is crucial for synapse development and that its disruption may lead to pathogenesis of neuropsychiatric disorders
We found that the interaction of ARHGAP33 with TrkB was significantly weakened in the SORT1-knockdown neurons (P 1⁄4 7.5 Â 10 À 4; Fig. 6f, Supplementary Fig. 4), suggesting that SORT1 is essential for the formation of ARHGAP33/TrkB/ SORT1 complexes (Fig. 6g)
Summary
Intracellular trafficking of receptor proteins is essential for neurons to detect various extracellular factors during the formation and refinement of neural circuits. ARHGAP33 knockout (KO) mice exhibit reduced expression of synaptic TrkB, impaired spine development and neuropsychiatric disorder-related behavioural abnormalities. These deficits are rescued by specific pharmacological enhancement of TrkB signalling in ARHGAP33 KO mice. These SNX proteins are highly enriched in the brain, but it remains unclear whether and how they are involved in protein sorting and trafficking in neurons and contribute to higher brain functions. TrkB is a high-affinity receptor for brain-derived neurotrophic factor (BDNF) that plays important roles in the neuronal development, establishment and maintenance of synapses, regulation of synaptic transmission and plasticity, and memory formation[14,15,16]. The isolated PSD fraction and total lysates of WT and ARHGAP33 KO mice were immunoblotted with anti-TrkB, anti-PSD-95, anti-SORT1, and anti-ARHGAP33 antibodies
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