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Abnormal development of dendritic spines in FMR1 knock-out mice
E A Nimchinsky1, A M Oberlander, K Svoboda
1Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. nimchins@cshl.org
Abstract:
Fragile X syndrome is caused by a mutation in the FMR1 gene leading to absence of the fragile X mental retardation protein (FMRP). Reports that patients and adult FMR1 knock-out mice have abnormally long dendritic spines of increased density suggested that the disorder might involve abnormal spine development. Because spine length, density, and motility change dramatically in the first postnatal weeks, we analyzed these properties in mutant mice and littermate controls at 1, 2, and 4 weeks of age. To label neurons, a viral vector carrying the enhanced green fluorescent protein gene was injected into the barrel cortex. Layer V neurons were imaged on a two-photon laser scanning microscope in fixed tissue sections. Analysis of >16,000 spines showed clear developmental patterns. Between 1 and 4 weeks of age, spine density increased 2.5-fold, and mean spine length decreased by 17% in normal animals. Early during cortical synaptogenesis, pyramidal cells in mutant mice had longer spines than controls. At 1 week, spine length was 28% greater in mutants than in controls. At 2 weeks, this difference was 10%, and at 4 weeks only 3%. Similarly, spine density was 33% greater in mutants than in controls at 1 week of age. At 2 or 4 weeks of age, differences were not detectable. The spine abnormality was not detected in neocortical organotypic cultures. The transient nature of the spine abnormality in the intact animal suggests that FMRP might play a role in the normal process of dendritic spine growth in coordination with the experience-dependent development of cortical circuits.
Insights
Fragile X syndrome, caused by FMR1 gene mutations, results in abnormal dendritic spine development. This study reveals transient spine abnormalities in mutant mice, suggesting FMRP
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Fragile X syndrome is linked to FMR1 gene mutations, causing absence of fragile X mental retardation protein (FMRP).
- Previous studies suggest abnormal dendritic spine development in Fragile X patients and FMR1 knockout mice.
Purpose of the Study:
- To investigate the developmental changes in dendritic spine length and density in FMR1 knockout mice during early postnatal weeks.
- To determine the role of FMRP in the experience-dependent development of cortical circuits and dendritic spine maturation.
Main Methods:
- Utilized a viral vector for enhanced green fluorescent protein (EGFP) labeling of layer V neurons in the barrel cortex of mutant and control mice.
- Employed two-photon laser scanning microscopy to image and analyze >16,000 dendritic spines at 1, 2, and 4 weeks postnatal.
- Compared spine morphology and density between FMR1 knockout mice and littermate controls.
Main Results:
- FMR1 knockout mice exhibited significantly longer and denser dendritic spines at 1 week of age compared to controls.
- These spine abnormalities were transient, with differences diminishing by 4 weeks of age in the intact animal.
- No spine abnormality was observed in neocortical organotypic cultures, indicating an in vivo developmental regulation.
Conclusions:
- The transient nature of dendritic spine abnormalities in FMR1 knockout mice suggests FMRP's crucial role in coordinating spine development with experience-dependent circuit maturation.
- Findings highlight a critical developmental window for FMRP function in regulating dendritic spine morphology.
