An activity-dependent determinant of synapse elimination in the mammalian brain

Neuron. 2021 Apr 21;109(8):1333-1349.e6. doi: 10.1016/j.neuron.2021.03.006. Epub 2021 Mar 25.


To establish functional neural circuits in the brain, synaptic connections are refined by neural activity during development, where active connections are maintained and inactive ones are eliminated. However, the molecular signals that regulate synapse refinement remain to be elucidated. When we inactivate a subset of neurons in the mouse cingulate cortex, their callosal connections are eliminated through activity-dependent competition. Using this system, we identify JAK2 tyrosine kinase as a key regulator of inactive synapse elimination. We show that JAK2 is necessary and sufficient for elimination of inactive connections; JAK2 is activated at inactive synapses in response to signals from other active synapses; STAT1, a substrate of JAK2, mediates inactive synapse elimination; JAK2 signaling is critical for physiological refinement of synapses during normal development; and JAK2 regulates synapse refinement in multiple brain regions. We propose that JAK2 is an activity-dependent switch that serves as a determinant of inactive synapse elimination.

Keywords: JAK2 kinase; STAT1; callosal synapse; competition; inactive synapse elimination; neural activity; retinogeniculate synapse; synapse refinement.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / physiology*
  • Janus Kinase 2 / metabolism*
  • Mice
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism
  • Neurons / physiology*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / physiology
  • Synapses / metabolism
  • Synapses / physiology*


  • STAT1 Transcription Factor
  • Janus Kinase 2