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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

Correlation analysis of morphological parameters of dendritic spines. Representative dot plots of spine morphological data. Data points representing individual spines from wild-type mice are highlighted with black dots and best-fit trend lines are black. Data points from fmr1-/y mice are highlighted in gray dots and best-fit trend lines are gray (n = 221 wild-type spines, n = 224 fmr1-/y spines). All Pearson R2 values are color-coded as above.
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Figure 8: Correlation analysis of morphological parameters of dendritic spines. Representative dot plots of spine morphological data. Data points representing individual spines from wild-type mice are highlighted with black dots and best-fit trend lines are black. Data points from fmr1-/y mice are highlighted in gray dots and best-fit trend lines are gray (n = 221 wild-type spines, n = 224 fmr1-/y spines). All Pearson R2 values are color-coded as above.

Mentions: The observed spine elongation on average by 25% could be due to alterations in neck length, head length or both (Figure 7A). An analysis of more than 220 intact spines per genotype revealed significantly longer spine necks in the fmr1-/y mice (684 ± 11 nm) compared to wild-type (518 ± 10 nm; p = 0.0003), due to a significantly greater number of long spines in the fmr1-y mice (Chi2 test p < 0.0001; Figures 7B,C). In contrast, spine neck width was similar between genotypes (wild-type = 140 ± 4.3 nm, fmr1-/y = 130 ± 9.8 nm, p = 0.79). Neck length correlated with spine length and neck area (Figures 8A,B). Neck area correlated with spine area (Figure 8C) and, accordingly, a larger spine neck area was found in fmr1-/y mice (0.13 ± 0.009 μm2) compared to wild-type (0.099 ± 0.005 μm2; p = 0.031) (Figure 7D). Conversely, no change in spine head length (wild-type = 338 ± 14 nm, fmr1-/y = 346 ± 10 nm; p = 0.68) or head area (wild-type = 0.12 ± 0.012 μm2, fmr1-/y = 0.14 ± 0.013 μm2; p = 0.48) was observed (Figures 7E–G). To investigate whether the specific alteration in spine neck morphology modified the relationship of distinct morphological parameters in the mouse model of Fragile X syndrome, we performed a detailed correlation analysis. In agreement with the fact that spine heads generally constitute the major bulk of spines (Arellano et al., 2007), spine head area correlated more strongly with total spine area than spine necks (Figures 8C,F). Nevertheless, there was still positive correlation between neck area and the total spine area (Figure 8C). Weak positive correlation was observed between neck width and spine area (Figure 8J). No correlation was found between neck length and head length (Figure 8G), neck length and head area (Figure 8H), and only a very weak negative correlation was found between neck width and neck length (Figure 8I). These data are remarkably similar to data recently reported in spines of living neurons imaged in wild-type mouse hippocampus (Tønnesen et al., 2014). Importantly, while both genotypes showed similar correlation between neck length and neck area (Figure 8B), and head length and head area (Figure 8E), the strength of correlation was significantly stronger in the fmr1-/y spines. Together with the distinct level of correlation between the head and neck lengths and the total spine length, these analyses point to the weighted contribution of the spine neck in determining total spine length (Figures 8A,D respectively). Collectively, these data (summarized in Table 1) reveal that FMRP loss leads to an increase in spine density and a specific elongation of the spine neck, but not the spine head in the accumbens.


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)

Correlation analysis of morphological parameters of dendritic spines. Representative dot plots of spine morphological data. Data points representing individual spines from wild-type mice are highlighted with black dots and best-fit trend lines are black. Data points from fmr1-/y mice are highlighted in gray dots and best-fit trend lines are gray (n = 221 wild-type spines, n = 224 fmr1-/y spines). All Pearson R2 values are color-coded as above.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4374460&req=5

Figure 8: Correlation analysis of morphological parameters of dendritic spines. Representative dot plots of spine morphological data. Data points representing individual spines from wild-type mice are highlighted with black dots and best-fit trend lines are black. Data points from fmr1-/y mice are highlighted in gray dots and best-fit trend lines are gray (n = 221 wild-type spines, n = 224 fmr1-/y spines). All Pearson R2 values are color-coded as above.
Mentions: The observed spine elongation on average by 25% could be due to alterations in neck length, head length or both (Figure 7A). An analysis of more than 220 intact spines per genotype revealed significantly longer spine necks in the fmr1-/y mice (684 ± 11 nm) compared to wild-type (518 ± 10 nm; p = 0.0003), due to a significantly greater number of long spines in the fmr1-y mice (Chi2 test p < 0.0001; Figures 7B,C). In contrast, spine neck width was similar between genotypes (wild-type = 140 ± 4.3 nm, fmr1-/y = 130 ± 9.8 nm, p = 0.79). Neck length correlated with spine length and neck area (Figures 8A,B). Neck area correlated with spine area (Figure 8C) and, accordingly, a larger spine neck area was found in fmr1-/y mice (0.13 ± 0.009 μm2) compared to wild-type (0.099 ± 0.005 μm2; p = 0.031) (Figure 7D). Conversely, no change in spine head length (wild-type = 338 ± 14 nm, fmr1-/y = 346 ± 10 nm; p = 0.68) or head area (wild-type = 0.12 ± 0.012 μm2, fmr1-/y = 0.14 ± 0.013 μm2; p = 0.48) was observed (Figures 7E–G). To investigate whether the specific alteration in spine neck morphology modified the relationship of distinct morphological parameters in the mouse model of Fragile X syndrome, we performed a detailed correlation analysis. In agreement with the fact that spine heads generally constitute the major bulk of spines (Arellano et al., 2007), spine head area correlated more strongly with total spine area than spine necks (Figures 8C,F). Nevertheless, there was still positive correlation between neck area and the total spine area (Figure 8C). Weak positive correlation was observed between neck width and spine area (Figure 8J). No correlation was found between neck length and head length (Figure 8G), neck length and head area (Figure 8H), and only a very weak negative correlation was found between neck width and neck length (Figure 8I). These data are remarkably similar to data recently reported in spines of living neurons imaged in wild-type mouse hippocampus (Tønnesen et al., 2014). Importantly, while both genotypes showed similar correlation between neck length and neck area (Figure 8B), and head length and head area (Figure 8E), the strength of correlation was significantly stronger in the fmr1-/y spines. Together with the distinct level of correlation between the head and neck lengths and the total spine length, these analyses point to the weighted contribution of the spine neck in determining total spine length (Figures 8A,D respectively). Collectively, these data (summarized in Table 1) reveal that FMRP loss leads to an increase in spine density and a specific elongation of the spine neck, but not the spine head in the accumbens.

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