Complement Component C3 Loss leads to Locomotor Deficits and Altered Cerebellar Internal Granule Cell In Vitro Synaptic Protein Expression in C57BL/6 Mice

Nicholas W. DeKorver, Tammy R. Chaudoin, Gang Zhao, Dong Wang, Jyothi Arikkath, Stephen J. Bonasera

Research output: Contribution to journalArticlepeer-review

Abstract

Complement component 3 (C3) expression is increased in the cerebellum of aging mice that demonstrate locomotor impairments and increased excitatory synapse density. However, C3 regulation of locomotion, as well as C3 roles in excitatory synapse function, remains poorly understood. Here, we demonstrate that constitutive loss of C3 function in mice evokes a locomotor phenotype characterized by decreased speed, increased active state locomotor probability, and gait ataxia. C3 loss does not alter metabolism or body mass composition. No evidence of significant muscle weakness or degenerative arthritis was found in C3 knockout mice to explain decreased gait speeds. In an enriched primary cerebellar granule cell culture model, loss of C3 protein results in increased excitatory synaptic density and increased response to KCl depolarization. Our analysis of excitatory synaptic density in the cerebellar internal granule cell and molecular layers did not demonstrate increased synaptic density in vivo, suggesting the presence of compensatory mechanisms regulating synaptic development. Functional deficits in C3 knockout mice are therefore more likely to result from altered synaptic function and/or connectivity than gross synaptic deficits. Our data demonstrate a novel role for complement proteins in cerebellar regulation of locomotor output and control.

Original languageEnglish (US)
Pages (from-to)5857-5875
Number of pages19
JournalMolecular Neurobiology
Volume58
Issue number11
DOIs
StatePublished - Nov 2021

Keywords

  • Ataxia
  • Bone density
  • C3
  • Cerebellum
  • Complement component 3
  • Gait speed
  • Grip strength
  • Internal granule cell
  • Microtomography
  • Vgat
  • Vglut1

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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