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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 density of excitatory synapses in the accumbens of fmr1-/y mice. Electron micrographs captured in the core of the nucleus accumbens of wild-type (A) and fmr1-/y mice (B) reveal the scattered distribution and different density of excitatory synapses in the two genotypes. These putative glutamatergic synapses were identified by the clear presence of a PSD as well as pre- (blue) and postsynaptic (red) compartments. Scale bars = 500 nm. (C) Mean PSD density values from 50 images per animal revealed a significant increase in excitatory synapse density in fmr1-/y mice (n = 3) compared to wild-type (n = 3). Unpaired t-test, p = 0.049. (D) Mean PSD lengths measured from 100 synapses per animal (n = 3) revealed identical PSD length in the two genotypes. Unpaired t-test, p = 0.422. (E) Separation of PSD length values into 100 nm bins followed by a Chi-squared test, revealed no difference in PSD length distribution, p = 0.670.
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Figure 5: Higher density of excitatory synapses in the accumbens of fmr1-/y mice. Electron micrographs captured in the core of the nucleus accumbens of wild-type (A) and fmr1-/y mice (B) reveal the scattered distribution and different density of excitatory synapses in the two genotypes. These putative glutamatergic synapses were identified by the clear presence of a PSD as well as pre- (blue) and postsynaptic (red) compartments. Scale bars = 500 nm. (C) Mean PSD density values from 50 images per animal revealed a significant increase in excitatory synapse density in fmr1-/y mice (n = 3) compared to wild-type (n = 3). Unpaired t-test, p = 0.049. (D) Mean PSD lengths measured from 100 synapses per animal (n = 3) revealed identical PSD length in the two genotypes. Unpaired t-test, p = 0.422. (E) Separation of PSD length values into 100 nm bins followed by a Chi-squared test, revealed no difference in PSD length distribution, p = 0.670.

Mentions: Recent results have demonstrated a tight correlation between spine morphology and synaptic strength (Araya et al., 2014; Tønnesen et al., 2014). Therefore, we next searched for structural alterations that could contribute to the impaired synaptic plasticity in fmr1-/y. Dendritic spine anomalies are common in neuropsychiatric diseases and constitute a core feature of intellectual disability (Penzes et al., 2011). A common finding in both human patients and mouse models of FRAX, is the higher number of spines in multiple brain regions (He and Portera-Cailliau, 2013). In line with these findings, we found that the density of excitatory synapses innervating spine heads was significantly increased on average by 28% in the accumbens of fmr1-/y mice (Figures 5A–C). Postsynaptic density (PSD) distribution in fmr1-/y mice (0.32 ± 0.02 PSD/μm2) was significantly denser than wild-type accumbens (0.25 ± 0.02 PSD/μm2; p = 0.049). In contrast, PSD length was similar (wild-type = 275 ± 3 nm, fmr1-/y = 289 ± 15 nm; p = 0.42) between genotypes (n = 300 synapses per genotype), suggesting that the increase in synapse number in the absence of FMRP is not the consequence of a potential sampling error of differentially sized PSDs (Figure 5D,E). To corroborate these observations, we also performed a 3D stereological approach to more accurately assess PSD density and size. This experiment confirmed our 2D analysis, showing an increased PSD density in the fmr1-/y mice (wild-type = 1.1 ± 0.2 PSDs/μm2, fmr1-/y = 1.7 ± 0.04 PSDs/μm2; p = 0.046), yet confirmed the similarity in the PSD area (wild-type = 0.036 ± 0.004 μm2, fmr1-/y = 0.039 ± 0.002 μm2; p = 0.64).


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 density of excitatory synapses in the accumbens of fmr1-/y mice. Electron micrographs captured in the core of the nucleus accumbens of wild-type (A) and fmr1-/y mice (B) reveal the scattered distribution and different density of excitatory synapses in the two genotypes. These putative glutamatergic synapses were identified by the clear presence of a PSD as well as pre- (blue) and postsynaptic (red) compartments. Scale bars = 500 nm. (C) Mean PSD density values from 50 images per animal revealed a significant increase in excitatory synapse density in fmr1-/y mice (n = 3) compared to wild-type (n = 3). Unpaired t-test, p = 0.049. (D) Mean PSD lengths measured from 100 synapses per animal (n = 3) revealed identical PSD length in the two genotypes. Unpaired t-test, p = 0.422. (E) Separation of PSD length values into 100 nm bins followed by a Chi-squared test, revealed no difference in PSD length distribution, p = 0.670.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Higher density of excitatory synapses in the accumbens of fmr1-/y mice. Electron micrographs captured in the core of the nucleus accumbens of wild-type (A) and fmr1-/y mice (B) reveal the scattered distribution and different density of excitatory synapses in the two genotypes. These putative glutamatergic synapses were identified by the clear presence of a PSD as well as pre- (blue) and postsynaptic (red) compartments. Scale bars = 500 nm. (C) Mean PSD density values from 50 images per animal revealed a significant increase in excitatory synapse density in fmr1-/y mice (n = 3) compared to wild-type (n = 3). Unpaired t-test, p = 0.049. (D) Mean PSD lengths measured from 100 synapses per animal (n = 3) revealed identical PSD length in the two genotypes. Unpaired t-test, p = 0.422. (E) Separation of PSD length values into 100 nm bins followed by a Chi-squared test, revealed no difference in PSD length distribution, p = 0.670.
Mentions: Recent results have demonstrated a tight correlation between spine morphology and synaptic strength (Araya et al., 2014; Tønnesen et al., 2014). Therefore, we next searched for structural alterations that could contribute to the impaired synaptic plasticity in fmr1-/y. Dendritic spine anomalies are common in neuropsychiatric diseases and constitute a core feature of intellectual disability (Penzes et al., 2011). A common finding in both human patients and mouse models of FRAX, is the higher number of spines in multiple brain regions (He and Portera-Cailliau, 2013). In line with these findings, we found that the density of excitatory synapses innervating spine heads was significantly increased on average by 28% in the accumbens of fmr1-/y mice (Figures 5A–C). Postsynaptic density (PSD) distribution in fmr1-/y mice (0.32 ± 0.02 PSD/μm2) was significantly denser than wild-type accumbens (0.25 ± 0.02 PSD/μm2; p = 0.049). In contrast, PSD length was similar (wild-type = 275 ± 3 nm, fmr1-/y = 289 ± 15 nm; p = 0.42) between genotypes (n = 300 synapses per genotype), suggesting that the increase in synapse number in the absence of FMRP is not the consequence of a potential sampling error of differentially sized PSDs (Figure 5D,E). To corroborate these observations, we also performed a 3D stereological approach to more accurately assess PSD density and size. This experiment confirmed our 2D analysis, showing an increased PSD density in the fmr1-/y mice (wild-type = 1.1 ± 0.2 PSDs/μm2, fmr1-/y = 1.7 ± 0.04 PSDs/μm2; p = 0.046), yet confirmed the similarity in the PSD area (wild-type = 0.036 ± 0.004 μm2, fmr1-/y = 0.039 ± 0.002 μm2; p = 0.64).

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