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 Ca2+ entry through Cav1.2 L-type Ca2+ channels, activation of the Ca2+-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. (C) 2010 Elsevier Inc. All rights reserved.