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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

Lack of LTP and augmented AMPA/NMDA ratio in accumbens MSN of fmr1-/y mice. (A) Representative experiment illustrating the lack of LTP in fmr1-/y mice. Inset shows EPSCs averaged over 10 min baseline and 20 min after the induction protocol respectively. (B) Averaged time-courses of LTP experiments for both genotypes. LTP was absent in fmr1-/y mice (p = 0.0415 Mann-Whitney test) (C) Representative current traces of a wild type (left) and fmr1-/y (right) MSN voltage clamped at −40 mV to illustrate the computation of A/N ratios. Black: Dual AMPA and NMDA response. Blue: isolated AMPA response after application of d-APV (50 μM). Red: NMDA response extracted via subtraction of AMPA response from the dual response. (D) A/N ratios were larger in fmr1-/y mice (p = 0.043, Mann-Whitney test).
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Figure 2: Lack of LTP and augmented AMPA/NMDA ratio in accumbens MSN of fmr1-/y mice. (A) Representative experiment illustrating the lack of LTP in fmr1-/y mice. Inset shows EPSCs averaged over 10 min baseline and 20 min after the induction protocol respectively. (B) Averaged time-courses of LTP experiments for both genotypes. LTP was absent in fmr1-/y mice (p = 0.0415 Mann-Whitney test) (C) Representative current traces of a wild type (left) and fmr1-/y (right) MSN voltage clamped at −40 mV to illustrate the computation of A/N ratios. Black: Dual AMPA and NMDA response. Blue: isolated AMPA response after application of d-APV (50 μM). Red: NMDA response extracted via subtraction of AMPA response from the dual response. (D) A/N ratios were larger in fmr1-/y mice (p = 0.043, Mann-Whitney test).

Mentions: To directly address this possibility and extend our previous work on LTD, we tested whether we could evoke LTP in fmr1-/y mice. Using our new STDP protocol, we found that NMDAR-mediated LTP was ablated in accumbens MSN of fmr1-/y mice compared to their wild type littermates (p = 0.0415 Mann-Whitney test; Figures 2A,B). In physiological and pathological conditions, long-term plasticity and the ratio of evoked synaptic AMPA/NMDA ratio often covariate (Gocel and Larson, 2012; Gipson et al., 2014). Ample evidence points toward protracted changes in the AMPA/NMDA ratio in rodent models of mental disability and autism. For example, in the in utero valproate exposure model of autism, we recently reported that adult rats had impaired prefrontal LTP and enhanced AMPA/NMDA ratio (Martin and Manzoni, 2014). Therefore, we next quantified and compared the ratio of evoked synaptic AMPAR and NMDAR currents (AMPA/NMDA ratio). We found that this index was augmented in fmr1-/y mice compared to their wild-type littermates (p = 0.043 Mann-Whitney test; Figures 2C,D).


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)

Lack of LTP and augmented AMPA/NMDA ratio in accumbens MSN of fmr1-/y mice. (A) Representative experiment illustrating the lack of LTP in fmr1-/y mice. Inset shows EPSCs averaged over 10 min baseline and 20 min after the induction protocol respectively. (B) Averaged time-courses of LTP experiments for both genotypes. LTP was absent in fmr1-/y mice (p = 0.0415 Mann-Whitney test) (C) Representative current traces of a wild type (left) and fmr1-/y (right) MSN voltage clamped at −40 mV to illustrate the computation of A/N ratios. Black: Dual AMPA and NMDA response. Blue: isolated AMPA response after application of d-APV (50 μM). Red: NMDA response extracted via subtraction of AMPA response from the dual response. (D) A/N ratios were larger in fmr1-/y mice (p = 0.043, Mann-Whitney test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Lack of LTP and augmented AMPA/NMDA ratio in accumbens MSN of fmr1-/y mice. (A) Representative experiment illustrating the lack of LTP in fmr1-/y mice. Inset shows EPSCs averaged over 10 min baseline and 20 min after the induction protocol respectively. (B) Averaged time-courses of LTP experiments for both genotypes. LTP was absent in fmr1-/y mice (p = 0.0415 Mann-Whitney test) (C) Representative current traces of a wild type (left) and fmr1-/y (right) MSN voltage clamped at −40 mV to illustrate the computation of A/N ratios. Black: Dual AMPA and NMDA response. Blue: isolated AMPA response after application of d-APV (50 μM). Red: NMDA response extracted via subtraction of AMPA response from the dual response. (D) A/N ratios were larger in fmr1-/y mice (p = 0.043, Mann-Whitney test).
Mentions: To directly address this possibility and extend our previous work on LTD, we tested whether we could evoke LTP in fmr1-/y mice. Using our new STDP protocol, we found that NMDAR-mediated LTP was ablated in accumbens MSN of fmr1-/y mice compared to their wild type littermates (p = 0.0415 Mann-Whitney test; Figures 2A,B). In physiological and pathological conditions, long-term plasticity and the ratio of evoked synaptic AMPA/NMDA ratio often covariate (Gocel and Larson, 2012; Gipson et al., 2014). Ample evidence points toward protracted changes in the AMPA/NMDA ratio in rodent models of mental disability and autism. For example, in the in utero valproate exposure model of autism, we recently reported that adult rats had impaired prefrontal LTP and enhanced AMPA/NMDA ratio (Martin and Manzoni, 2014). Therefore, we next quantified and compared the ratio of evoked synaptic AMPAR and NMDAR currents (AMPA/NMDA ratio). We found that this index was augmented in fmr1-/y mice compared to their wild-type littermates (p = 0.043 Mann-Whitney test; Figures 2C,D).

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