Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.
Psychiatric and neurodevelopmental disorders may arise from anomalies in long-range neuronal connectivity downstream of pathologies in dendritic spines. However, the mechanisms that may link spine pathology to circuit abnormalities relevant to atypical behavior remain unknown. Using a mouse model to conditionally disrupt a critical regulator of the dendritic spine cytoskeleton, the actin-related protein 2/3 complex (Arp2/3), we report here a molecular mechanism that unexpectedly reveals the inter-relationship of progressive spine pruning, elevated frontal cortical excitation of pyramidal neurons and striatal hyperdopaminergia in a cortical-to-midbrain circuit abnormality. The main symptomatic manifestations of this circuit abnormality are psychomotor agitation and stereotypical behaviors, which are relieved by antipsychotics. Moreover, this antipsychotic-responsive locomotion can be mimicked in wild-type mice by optogenetic activation of this circuit. Collectively these results reveal molecular and neural-circuit mechanisms, illustrating how diverse pathologies may converge to drive behaviors relevant to psychiatric disorders.
Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA.
Il Hwan
IH
Kim
Department of Psychology and Neuroscience, Duke University Medical School, Durham, North Carolina, USA.
Mark A
MA
Rossi
1] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina, USA. [2] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina.
Dipendra K
DK
Aryal
1] Department of Anatomy and Histology, Szent István University, Budapest, Hungary. [2] Faculty of Veterinary Science, Szent István University, Budapest, Hungary.
Bence
B
Racz
Department of Psychology and Neuroscience, Duke University Medical School, Durham, North Carolina, USA.
Namsoo
N
Kim
Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA.
Akiyoshi
A
Uezu
Department of Neurobiology, Duke University Medical School, Durham, North Carolina, USA.
Fan
F
Wang
1] Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA. [2] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina, USA. [3] Department of Psychiatry and Behavioral Sciences, Duke University Medical School, Durham, North Carolina. [4] Department of Neurobiology, Duke University Medical School, Durham, North Carolina, USA.
William C
WC
Wetsel
1] Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, USA. [2] Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Richard J
RJ
Weinberg
Department of Psychology and Neuroscience, Duke University Medical School, Durham, North Carolina, USA.
Henry
H
Yin
1] Department of Cell Biology, Duke University Medical School, Durham, North Carolina, USA. [2] Department of Neurobiology, Duke University Medical School, Durham, North Carolina, USA.
Scott H
SH
Soderling
D051378:Actin-Related Protein 3 / Q000235:genetics / Q000378:metabolism; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D049229:Dendritic Spines / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism*; D062308:Optogenetics; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects; D011595:Psychomotor Agitation / Q000523:psychology; D017966:Pyramidal Cells / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects
D051378:Actin-Related Protein 3; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D014150:Antipsychotic Agents; D004298:Dopamine