Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice

Xi Cheng; Yu Tang; D J Vidyadhara; Ben-Zheng Li; Michael Zimmerman; Alexandr Pak; Sanghamitra Nareddula; Paige Alyssa Edens; Sreeganga S Chandra; Alexander A Chubykin

doi:10.1016/j.isci.2023.107842

Impaired pre-synaptic plasticity and visual responses in auxilin-knockout mice

iScience. 2023 Sep 6;26(10):107842. doi: 10.1016/j.isci.2023.107842. eCollection 2023 Oct 20.

Authors

Xi Cheng¹, Yu Tang¹, D J Vidyadhara^{2

3}, Ben-Zheng Li^{4

5}, Michael Zimmerman^{1

6}, Alexandr Pak¹, Sanghamitra Nareddula¹, Paige Alyssa Edens¹, Sreeganga S Chandra^{2

3

7}, Alexander A Chubykin¹

Affiliations

¹ Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA.
² Department of Neurology, Yale University, CT, USA.
³ Department of Neuroscience, Yale University, CT, USA.
⁴ Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵ Department of Electrical Engineering, University of Colorado, Denver, Denver, CO, USA.
⁶ Department of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
⁷ Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, CT, USA.

Abstract

Auxilin (DNAJC6/PARK19), an endocytic co-chaperone, is essential for maintaining homeostasis in the readily releasable pool (RRP) by aiding clathrin-mediated uncoating of synaptic vesicles. Its loss-of-function mutations, observed in familial Parkinson's disease (PD), lead to basal ganglia motor deficits and cortical dysfunction. We discovered that auxilin-knockout (Aux-KO) mice exhibited impaired pre-synaptic plasticity in layer 4 to layer 2/3 pyramidal cell synapses in the primary visual cortex (V1), including reduced short-term facilitation and depression. Computational modeling revealed increased RRP refilling during short repetitive stimulation, which diminished during prolonged stimulation. Silicon probe recordings in V1 of Aux-KO mice demonstrated disrupted visual cortical circuit responses, including reduced orientation selectivity, compromised visual mismatch negativity, and shorter visual familiarity-evoked theta oscillations. Pupillometry analysis revealed an impaired optokinetic response. Auxilin-dependent pre-synaptic endocytosis dysfunction was associated with deficits in pre-synaptic plasticity, visual cortical functions, and eye movement prodromally or at the early stage of motor symptoms.

Keywords: Biological sciences; Natural sciences; Neuroscience; Physiology.

Grants and funding

R01 MH116500/MH/NIMH NIH HHS/United States