Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior

Cell Rep. 2020 Feb 18;30(7):2374-2386.e5. doi: 10.1016/j.celrep.2020.01.084.


The neurodevelopmental origin of hyperactivity disorder has been suggested to involve the dopaminergic system, but the underlying mechanisms are still unknown. Here, transcription factors Lmx1a and Lmx1b are shown to be essential for midbrain dopaminergic (mDA) neuron excitatory synaptic inputs and dendritic development. Strikingly, conditional knockout (cKO) of Lmx1a/b in postmitotic mDA neurons results in marked hyperactivity. In seeking Lmx1a/b target genes, we identify positively regulated Slitrk2 and negatively regulated Slitrk5. These two synaptic adhesion proteins promote excitatory and inhibitory synapses on mDA neurons, respectively. Knocking down Slitrk2 reproduces some of the Lmx1a/b cKO cellular and behavioral phenotypes, whereas Slitrk5 knockdown has opposite effects. The hyperactivity caused by this imbalance in excitatory/inhibitory synaptic inputs on dopamine neurons is reproduced by chronically inhibiting the ventral tegmental area during development using pharmacogenetics. Our study shows that alterations in developing dopaminergic circuits strongly impact locomotor activity, shedding light on mechanisms causing hyperactivity behaviors.

Keywords: DREADD; Sholl analysis; VTA; critical period; dendrite; development; locomotion; mice; pharmacogenetic; primary culture.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Excitatory Postsynaptic Potentials
  • Female
  • Humans
  • Inhibitory Postsynaptic Potentials
  • LIM-Homeodomain Proteins / metabolism
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / metabolism*
  • Pregnancy
  • Primary Cell Culture
  • Psychomotor Agitation / metabolism*
  • Psychomotor Agitation / pathology
  • Synapses / metabolism*
  • Synapses / pathology
  • Transcription Factors / metabolism
  • Transfection


  • LIM homeobox transcription factor 1 beta
  • LIM-Homeodomain Proteins
  • Lmx1a protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Slitrk protein, mouse
  • Slitrk5 protein, mouse
  • Transcription Factors