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Early postnatal plasticity in neocortex of Fmr1 knockout mice
Niraj S Desai1, Tanya M Casimiro, Stephen M Gruber
1The Neurosciences Fine Institute, San Diego, CA 92121, USA. desai@nsi.edu
Insights
Fragile X syndrome, caused by Fmr1 gene defects, alters brain development. This study reveals Fmr1 disruption selectively impairs synaptic plasticity in developing mouse neocortex, impacting long-term potentiation.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Fragile X syndrome results from Fmr1 gene defects, leading to abnormal dendritic spine morphology in the neocortex.
- Spine abnormalities are prominent early in life, suggesting developmental plasticity alterations contribute to behavioral phenotypes.
Purpose of the Study:
- To investigate the impact of Fmr1 gene disruption on two key forms of developmental plasticity in the early postnatal mouse neocortex.
- To determine if Fmr1 affects intrinsic and/or synaptic plasticity during critical developmental periods.
Main Methods:
- Utilized intracellular recordings in neocortical brain slices from early postnatal Fmr1 knockout mice.
- Examined long-term potentiation of intrinsic excitability (mGluR5-dependent) and spike timing-dependent plasticity (NMDA receptor-dependent).
Main Results:
- Intrinsic plasticity remained unaffected in Fmr1 knockout mice.
- Synaptic plasticity showed a striking alteration: long-term depression was robust, but long-term potentiation was completely absent.
- Fmr1 disruption exhibits selective effects on different forms of neural plasticity.
Conclusions:
- Fmr1 plays a critical role in regulating synaptic plasticity during early postnatal development.
- Altered postnatal development, specifically impaired synaptic plasticity, is a significant component of Fragile X syndrome.
- These findings highlight the selective nature of Fmr1's influence on neural plasticity and its implications for the disorder.
Abstract:
Fragile X syndrome is produced by a defect in a single X-linked gene, called Fmr1, and is characterized by abnormal dendritic spine morphologies with spines that are longer and thinner in neocortex than those from age-matched controls. Studies using Fmr1 knockout mice indicate that spine abnormalities are especially pronounced in the first month of life, suggesting that altered developmental plasticity underlies some of the behavioral phenotypes associated with the syndrome. To address this issue, we used intracellular recordings in neocortical slices from early postnatal mice to examine the effects of Fmr1 disruption on two forms of plasticity active during development. One of these, long-term potentiation of intrinsic excitability, is intrinsic in expression and requires mGluR5 activation. The other, spike timing-dependent plasticity, is synaptic in expression and requires N-methyl-d-aspartate receptor activation. While intrinsic plasticity was normal in the knockout mice, synaptic plasticity was altered in an unusual and striking way: long-term depression was robust but long-term potentiation was entirely absent. These findings underscore the ideas that Fmr1 has highly selective effects on plasticity and that abnormal postnatal development is an important component of the disorder.
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