MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons.
Striatal dopamine depletion profoundly reduces the density of spines and corticostriatal glutamatergic synapses formed on D(2) dopamine receptor expressing striatopallidal medium spiny neurons, leaving D(1) receptor expressing striatonigral medium spiny neurons relatively intact. Because D(2) dopamine receptors diminish the excitability of striatopallidal MSNs, the pruning of synapses could be a form of homeostatic plasticity aimed at restoring activity into a preferred range. To characterize the homeostatic mechanisms controlling synapse density in striatal medium spiny neurons, striatum from transgenic mice expressing a D(2) receptor reporter construct was co-cultured with wild-type cerebral cortex. Sustained depolarization of these co-cultures induced a profound pruning of glutamatergic synapses and spines in striatopallidal medium spiny neurons. This pruning was dependent upon Ca(2+) entry through Cav1.2 L-type Ca(2+) channels, activation of the Ca(2+)-dependent protein phosphatase calcineurin and up-regulation of myocyte enhancer factor 2 (MEF2) transcriptional activity. Depolarization and MEF2 up-regulation increased the expression of two genes linked to synaptic remodeling-Nur77 and Arc. Taken together, these studies establish a translational framework within which striatal adaptations linked to the symptoms of Parkinson's disease can be explored.
Tian
Xinyong
X
Department of Physiology Feinberg School of Medicine Northwestern University 303 E. Chicago Ave., Chicago, IL 60611, USA.
Kai
Li
L
Hockberger
Philip E
PE
Wokosin
David L
DL
Surmeier
D James
DJ
D000200:Action Potentials / Q000235:genetics; D000222:Adaptation, Physiological / Q000235:genetics; D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism; D004525:Efferent Pathways / Q000166:cytology / Q000378:metabolism; D005917:Globus Pallidus / Q000166:cytology / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D018006:Myogenic Regulatory Factors / Q000235:genetics*; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000235:genetics*
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D003598:Cytoskeletal Proteins; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D009419:Nerve Tissue Proteins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017448:Receptors, Dopamine D2; C092069:activity regulated cytoskeletal-associated protein; D018698:Glutamic Acid; D019703:Calcineurin; D004298:Dopamine