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Functional and structural deficits at accumbens synapses in a mouse model of Fragile X.

Neuhofer D, Henstridge CM, Dudok B, Sepers M, Lassalle O, Katona I, Manzoni OJ - Front Cell Neurosci (2015)

Bottom Line: In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents.Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens.These findings together reveal new structural and functional synaptic deficits in Fragile X.

View Article: PubMed Central - PubMed

Affiliation: INSERM U901 Marseille, France ; INMED Marseille, France ; Université de Aix-Marseille, UMR S901 Marseille, France.

ABSTRACT
Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP), a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP) of excitatory afferent inputs of medium spiny neurons (MSN) in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens. These findings together reveal new structural and functional synaptic deficits in Fragile X.

No MeSH data available.


Related in: MedlinePlus

Higher incidence of elongated spines in the accumbens of fmr1-/y mice. (A) Electron micrograph of a typical “mushroom” spine from the accumbens of a wild-type mouse. Scale bar = 100 nm. (B) Electron micrograph of longer, spines found in the accumbens of an fmr1-/y mouse. Presynaptic terminals are highlighted in blue, postsynaptic spine(s) labeled in red. Scale bar = 100 nm. (C) Analysis of mean spine length (n = 3 WT, n = 3 fmr1-/y) uncovered the presence of longer spines in the fmr1-/y mice. Unpaired t-test, p = 0.001. (D) Binned data from all 221 wild-type and 224 fmr1-/y spines reveals an increase in the number of long spines in fmr1-/y mice and a decrease in small spines compared to wild-type. Chi-squared test, p < 0.0001. Although the difference in the mean area of wild-type and fmr1-/y spines did not reach statistical significance (E); 3 WT v 3 fmr1-/y mice, unpaired t-test, p = 0.157), binning the data from all spines (221 WT v 224 fmr1-/y), revealed a rightward shift in the data distribution, due to a higher incidence of larger spines in fmr1-/y compared to wild-type (F). Chi-squared test, p = 0.0002.
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Figure 6: Higher incidence of elongated spines in the accumbens of fmr1-/y mice. (A) Electron micrograph of a typical “mushroom” spine from the accumbens of a wild-type mouse. Scale bar = 100 nm. (B) Electron micrograph of longer, spines found in the accumbens of an fmr1-/y mouse. Presynaptic terminals are highlighted in blue, postsynaptic spine(s) labeled in red. Scale bar = 100 nm. (C) Analysis of mean spine length (n = 3 WT, n = 3 fmr1-/y) uncovered the presence of longer spines in the fmr1-/y mice. Unpaired t-test, p = 0.001. (D) Binned data from all 221 wild-type and 224 fmr1-/y spines reveals an increase in the number of long spines in fmr1-/y mice and a decrease in small spines compared to wild-type. Chi-squared test, p < 0.0001. Although the difference in the mean area of wild-type and fmr1-/y spines did not reach statistical significance (E); 3 WT v 3 fmr1-/y mice, unpaired t-test, p = 0.157), binning the data from all spines (221 WT v 224 fmr1-/y), revealed a rightward shift in the data distribution, due to a higher incidence of larger spines in fmr1-/y compared to wild-type (F). Chi-squared test, p = 0.0002.

Mentions: In addition to the higher spine number, we uncovered a significant increase in the total length of fmr1-/y spines (Figures 6A–C) in the accumbens (wild-type = 856 ± 4 nm, fmr1-/y = 1069 ± 20 nm; p = 0.001). This manifest as a greater number of spines longer than 1 μm (wild-type = 60/221, fmr1-/y = 115/224) and fewer spines shorter than 1 μm (wild-type = 161/221, fmr1-/y = 109/224) in fmr1-/y accumbens compared to wild-type (Figure 6D). Interestingly, the differences in total cross-sectional spine area did not reach statistical significance (p = 0.157) between wild-type (0.22 ± 0.02 μm2) and fmr1-/y (0.27 ± 0.02 μm2) (Figure 6E). However, when total spine area was pooled within genotypes and the Data distribution analyzed, there was a significant increase in the number of larger spines observed in fmr1-/y mice (Chi2 test p = 0.0002; Figure 6F).


Functional and structural deficits at accumbens synapses in a mouse model of Fragile X.

Neuhofer D, Henstridge CM, Dudok B, Sepers M, Lassalle O, Katona I, Manzoni OJ - Front Cell Neurosci (2015)

Higher incidence of elongated spines in the accumbens of fmr1-/y mice. (A) Electron micrograph of a typical “mushroom” spine from the accumbens of a wild-type mouse. Scale bar = 100 nm. (B) Electron micrograph of longer, spines found in the accumbens of an fmr1-/y mouse. Presynaptic terminals are highlighted in blue, postsynaptic spine(s) labeled in red. Scale bar = 100 nm. (C) Analysis of mean spine length (n = 3 WT, n = 3 fmr1-/y) uncovered the presence of longer spines in the fmr1-/y mice. Unpaired t-test, p = 0.001. (D) Binned data from all 221 wild-type and 224 fmr1-/y spines reveals an increase in the number of long spines in fmr1-/y mice and a decrease in small spines compared to wild-type. Chi-squared test, p < 0.0001. Although the difference in the mean area of wild-type and fmr1-/y spines did not reach statistical significance (E); 3 WT v 3 fmr1-/y mice, unpaired t-test, p = 0.157), binning the data from all spines (221 WT v 224 fmr1-/y), revealed a rightward shift in the data distribution, due to a higher incidence of larger spines in fmr1-/y compared to wild-type (F). Chi-squared test, p = 0.0002.
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Related In: Results  -  Collection

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Figure 6: Higher incidence of elongated spines in the accumbens of fmr1-/y mice. (A) Electron micrograph of a typical “mushroom” spine from the accumbens of a wild-type mouse. Scale bar = 100 nm. (B) Electron micrograph of longer, spines found in the accumbens of an fmr1-/y mouse. Presynaptic terminals are highlighted in blue, postsynaptic spine(s) labeled in red. Scale bar = 100 nm. (C) Analysis of mean spine length (n = 3 WT, n = 3 fmr1-/y) uncovered the presence of longer spines in the fmr1-/y mice. Unpaired t-test, p = 0.001. (D) Binned data from all 221 wild-type and 224 fmr1-/y spines reveals an increase in the number of long spines in fmr1-/y mice and a decrease in small spines compared to wild-type. Chi-squared test, p < 0.0001. Although the difference in the mean area of wild-type and fmr1-/y spines did not reach statistical significance (E); 3 WT v 3 fmr1-/y mice, unpaired t-test, p = 0.157), binning the data from all spines (221 WT v 224 fmr1-/y), revealed a rightward shift in the data distribution, due to a higher incidence of larger spines in fmr1-/y compared to wild-type (F). Chi-squared test, p = 0.0002.
Mentions: In addition to the higher spine number, we uncovered a significant increase in the total length of fmr1-/y spines (Figures 6A–C) in the accumbens (wild-type = 856 ± 4 nm, fmr1-/y = 1069 ± 20 nm; p = 0.001). This manifest as a greater number of spines longer than 1 μm (wild-type = 60/221, fmr1-/y = 115/224) and fewer spines shorter than 1 μm (wild-type = 161/221, fmr1-/y = 109/224) in fmr1-/y accumbens compared to wild-type (Figure 6D). Interestingly, the differences in total cross-sectional spine area did not reach statistical significance (p = 0.157) between wild-type (0.22 ± 0.02 μm2) and fmr1-/y (0.27 ± 0.02 μm2) (Figure 6E). However, when total spine area was pooled within genotypes and the Data distribution analyzed, there was a significant increase in the number of larger spines observed in fmr1-/y mice (Chi2 test p = 0.0002; Figure 6F).

Bottom Line: In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents.Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens.These findings together reveal new structural and functional synaptic deficits in Fragile X.

View Article: PubMed Central - PubMed

Affiliation: INSERM U901 Marseille, France ; INMED Marseille, France ; Université de Aix-Marseille, UMR S901 Marseille, France.

ABSTRACT
Fragile X is the most common cause of inherited intellectual disability and a leading cause of autism. The disease is caused by mutation of a single X-linked gene called fmr1 that codes for the Fragile X mental retardation protein (FMRP), a 71 kDa protein, which acts mainly as a translation inhibitor. Fragile X patients suffer from cognitive and emotional deficits that coincide with abnormalities in dendritic spines. Changes in spine morphology are often associated with altered excitatory transmission and long-term plasticity, the most prominent deficit in fmr1-/y mice. The nucleus accumbens, a central part of the mesocortico-limbic reward pathway, is now considered as a core structure in the control of social behaviors. Although the socio-affective impairments observed in Fragile X suggest dysfunctions in the accumbens, the impact of the lack of FMRP on accumbal synapses has scarcely been studied. Here we report for the first time a new spike timing-dependent plasticity paradigm that reliably triggers NMDAR-dependent long-term potentiation (LTP) of excitatory afferent inputs of medium spiny neurons (MSN) in the nucleus accumbens core region. Notably, we discovered that this LTP was completely absent in fmr1-/y mice. In the fmr1-/y accumbens intrinsic membrane properties of MSNs and basal excitatory neurotransmission remained intact in the fmr1-/y accumbens but the deficit in LTP was accompanied by an increase in evoked AMPA/NMDA ratio and a concomitant reduction of spontaneous NMDAR-mediated currents. In agreement with these physiological findings, we found significantly more filopodial spines in fmr1-/y mice by using an ultrastructural electron microscopic analysis of accumbens core medium spiny neuron spines. Surprisingly, spine elongation was specifically due to the longer longitudinal axis and larger area of spine necks, whereas spine head morphology and postsynaptic density size on spine heads remained unaffected in the fmr1-/y accumbens. These findings together reveal new structural and functional synaptic deficits in Fragile X.

No MeSH data available.


Related in: MedlinePlus