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Published on: May 12, 2015
Altered hippocampal synaptic plasticity in the FMR1 gene family knockout mouse models
Jing Zhang1, Lingfei Hou, Eric Klann
1Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, Houston, TX 77030, USA.
Abstract:
Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 (FMR1) gene. FMR1 and its two paralogs, fragile X-related genes 1 and 2 (FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice. We found that metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/Fxr2 double knockout mice at young ages (4-6 wk old). In addition, Fmr1/Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4-6 mo of age. Interestingly, although Fmr1/Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.
Insights
Fragile X syndrome (FXS) involves the FMR1 gene and FMRP protein. This study shows FMRP and FXR2P impact synaptic plasticity, affecting mGluR-LTD and presynaptic function, suggesting cooperative roles in neural pathways.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Fragile X syndrome (FXS) is a leading inherited cause of intellectual disability.
- FXS arises from the absence of fragile X mental retardation protein (FMRP), encoded by the FMR1 gene.
- The FMR1 gene and its paralogs FXR1 and FXR2 form the Fmr1 gene family, implicated in neural development.
Purpose of the Study:
- To investigate the roles of FMRP and FXR2P in synaptic plasticity.
- To compare the effects of Fmr1, Fxr2, and combined Fmr1/Fxr2 gene knockout on synaptic function in mice.
Main Methods:
- Utilized knockout mouse models: Fmr1, Fxr2, and Fmr1/Fxr2 double knockouts.
- Assessed long-lasting synaptic plasticity, including metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) and late-phase long-term potentiation (L-LTP).
- Examined baseline synaptic transmission and short-term presynaptic plasticity.
Main Results:
- mGluR-LTD was impaired in young Fmr1, Fxr2, and Fmr1/Fxr2 knockout mice.
- Fmr1/Fxr2 double knockout mice showed deficits in baseline and short-term presynaptic plasticity, indicating cooperative function of FMRP and FXR2P.
- L-LTP remained unaltered in all knockout groups at older ages, but mGluR-LTD showed differential protein synthesis dependence.
- Fxr2 knockout mice exhibited reduced mGluR-LTD requiring protein synthesis, distinct from Fmr1 knockout mice.
Conclusions:
- Both FMRP and FXR2P play significant roles in regulating synaptic plasticity.
- FMRP and FXR2P appear to function in related yet independent pathways governing synaptic transmission and plasticity.
- These findings contribute to understanding the molecular mechanisms underlying FXS and related neurodevelopmental disorders.
