The short-time structural plasticity of dendritic spines is altered in a model of Rett syndrome (original) (raw)

The maturation of excitatory transmission comes about through a developmental period in which dendritic spines are highly motile and their number, form and size are rapidly changing. Surprisingly, although these processes are crucial for the formation of cortical circuitry, little is known about possible alterations of these processes in brain disease. By means of acute in vivo 2-photon imaging we show that the dynamic properties of dendritic spines of layer V cortical neurons are deeply affected in a mouse model of Rett syndrome (RTT) at a time around P25 when the neuronal phenotype of the disease is still mild. Then, we show that 24h after a subcutaneous injection of IGF-1 spine dynamics is restored. Our study demonstrates that spine dynamics in RTT mice is severely impaired early during development and suggest that treatments for RTT should be started very early in order to reestablish a normal period of spine plasticity. R ett syndrome (RTT) is a neurodevelopmental disorder characterized by a period of apparently normal development of 6-18 months followed by regression and onset of a variety of symptoms including motor abnormalities, mental retardation, epilepsy and anxiety 1 . Most cases of RTT involve mutations of methyl-CpG-binding protein 2 (MeCP2), a gene encoding a methylated DNA-binding protein that regulates gene transcription, mRNA splicing and chromatin structure 2 . However, how these genetic defects translate into RTT symptoms is still unknown. It has been proposed that synaptic alterations constitute a main substrate of the disease symptoms 3,4 , but only subtle alterations of neuronal density, dendritic arborisation and number of dendritic spines (the main site of excitatory synapses) were found in both patients 5,6 and mouse models in which MeCP2 has been deleted 7 . So far, the available studies 7 have been performed in fixed tissue thus not allowing the visualization of the dynamic processes underlying juvenile dendritic spine maturation. These involve the formation and removal of highly motile filopodia that can be stabilized and transformed into more stable mature spines. These processes can occur in a time scale of minutes and they are altered in response to manipulations that do not lead to manifest variations of spine density, suggesting that the short-time dynamic regulation of spine structure plays an important role in shaping connectivity of neural circuits 8 . To fill this gap, we analyzed dendritic spine dynamics in somatosensory cortex by 2-photon time lapse imaging in MeCP2 null mice crossed with Thy-GFP line 9,10 . At the onset of the disease (3-4 weeks of age 11,12 ) we found deep alterations in the dynamics of dendritic spines and filopodia. Later on at P40 when the maturation of the connectivity in the somatosensory cortex is complete, the dynamics of dendritic spines in RTT mice was identical to control, although a reduction in spine density was observed in mutants. Finally, we found that 24 hrs after a single subcutaneous injection of IGF-1, a molecule known to pass the blood brain barrier (BBB 13 ) and of proposed therapeutic potential in RTT 14-16 , spine motility was completely restored in the cerebral cortex of RTT mice.