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
Affiliations
Xi Cheng
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA
Yu Tang
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA
D.J. Vidyadhara
Department of Neurology, Yale University, CT, USA; Department of Neuroscience, Yale University, CT, USA
Ben-Zheng Li
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Electrical Engineering, University of Colorado, Denver, Denver, CO, USA
Michael Zimmerman
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA; Department of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA
Alexandr Pak
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA
Sanghamitra Nareddula
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA
Paige Alyssa Edens
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA
Sreeganga S. Chandra
Department of Neurology, Yale University, CT, USA; Department of Neuroscience, Yale University, CT, USA; Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University, CT, USA; Corresponding author
Alexander A. Chubykin
Department of Biological Sciences, Purdue Institute for Integrative Neuroscience, Purdue Autism Research Center, Purdue University, West Lafayette, IN 47907, USA; Corresponding author
Summary: 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.
