Abstract：
: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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Salesse C,Charest J,Doucet-Beaupré H,Castonguay AM,Labrecque S,De Koninck P,Lévesque Mdoi
10.1016/j.celrep.2020.01.084subject
Has Abstractpub_date
2020-02-18 00:00:00pages
2374-2386.e5issue
7issn
2211-1247pii
S2211-1247(20)30118-2journal_volume
30pub_type
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