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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

Similar excitability profile in wild-type and fmr1-/y medium spiny neurons. (A) Representative traces of voltage responses to somatic current injections of a wild-type (upper panel, WT) and fmr1-/y (lower panel) medium spiny neuron. (B) The voltage responses to hyperpolarizing current pulses revealed no differences in input resistance or inward rectification between the two genotypes (p = 0.2770, two way ANOVA; WT n = 40, black symbols; fmr1-/y n = 30, white symbols). (C) The number of action potentials as a function of depolarizing current injections was similar (p = 0.1272, two way ANOVA). (D) The firing probability plotted as a function of the EPSP slope revealed no changes in the Excitation-Spike coupling (p = 0.1488, two way ANOVA; WT n = 8, black symbols; fmr1-/y n = 5, white symbols).
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Figure 3: Similar excitability profile in wild-type and fmr1-/y medium spiny neurons. (A) Representative traces of voltage responses to somatic current injections of a wild-type (upper panel, WT) and fmr1-/y (lower panel) medium spiny neuron. (B) The voltage responses to hyperpolarizing current pulses revealed no differences in input resistance or inward rectification between the two genotypes (p = 0.2770, two way ANOVA; WT n = 40, black symbols; fmr1-/y n = 30, white symbols). (C) The number of action potentials as a function of depolarizing current injections was similar (p = 0.1272, two way ANOVA). (D) The firing probability plotted as a function of the EPSP slope revealed no changes in the Excitation-Spike coupling (p = 0.1488, two way ANOVA; WT n = 8, black symbols; fmr1-/y n = 5, white symbols).

Mentions: The lack of LTP in fmr1-/y mice could be caused by alterations of intrinsic and/or firing properties of the MSNs. Thus, we compared some of the basic properties of these neurons. Independently of their genotypes, all recorded MSNs showed similar membrane response profiles in response to a series of somatic current steps as shown in superimposable I-V plots (p = 0.2770, two way ANOVA; Figures 3A,B). The number of action potentials in response to somatic current steps was also similar in wild-type and fmr1-/y mice (p = 0.1272, two way ANOVA; Figure 3C). Furthermore the lack of LTP cannot be explained by different spiking in response to the LTP protocol. The jitter i.e., the standard deviation of spike timing was 1.25 ± 0.38 SD and 1.308 ± 0.93 SD for wild-type and in fmr1-/y mice respectively (p = 0.8503, Student’s unpaired t-test). We also determined the excitatory postsynaptic potential-spike coupling (or E-S coupling) to directly evaluate how synaptic excitation is integrated to generate an action potential in wild-type and fmr1-/y littermates (Thomazeau et al., 2014). We found that the E-S coupling was similar in wild-type and in fmr1-/y mice (p = 0.1488, two way ANOVA, Figure 3D). We conclude that the lack of FMRP in fmr1-/y mice has no major effect on excitatory synaptic integration in accumbens MSNs. More generally, the data indicate that the lack of FMRP expression did not affect on the intrinsic properties of accumbens MSNs.


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)

Similar excitability profile in wild-type and fmr1-/y medium spiny neurons. (A) Representative traces of voltage responses to somatic current injections of a wild-type (upper panel, WT) and fmr1-/y (lower panel) medium spiny neuron. (B) The voltage responses to hyperpolarizing current pulses revealed no differences in input resistance or inward rectification between the two genotypes (p = 0.2770, two way ANOVA; WT n = 40, black symbols; fmr1-/y n = 30, white symbols). (C) The number of action potentials as a function of depolarizing current injections was similar (p = 0.1272, two way ANOVA). (D) The firing probability plotted as a function of the EPSP slope revealed no changes in the Excitation-Spike coupling (p = 0.1488, two way ANOVA; WT n = 8, black symbols; fmr1-/y n = 5, white symbols).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Similar excitability profile in wild-type and fmr1-/y medium spiny neurons. (A) Representative traces of voltage responses to somatic current injections of a wild-type (upper panel, WT) and fmr1-/y (lower panel) medium spiny neuron. (B) The voltage responses to hyperpolarizing current pulses revealed no differences in input resistance or inward rectification between the two genotypes (p = 0.2770, two way ANOVA; WT n = 40, black symbols; fmr1-/y n = 30, white symbols). (C) The number of action potentials as a function of depolarizing current injections was similar (p = 0.1272, two way ANOVA). (D) The firing probability plotted as a function of the EPSP slope revealed no changes in the Excitation-Spike coupling (p = 0.1488, two way ANOVA; WT n = 8, black symbols; fmr1-/y n = 5, white symbols).
Mentions: The lack of LTP in fmr1-/y mice could be caused by alterations of intrinsic and/or firing properties of the MSNs. Thus, we compared some of the basic properties of these neurons. Independently of their genotypes, all recorded MSNs showed similar membrane response profiles in response to a series of somatic current steps as shown in superimposable I-V plots (p = 0.2770, two way ANOVA; Figures 3A,B). The number of action potentials in response to somatic current steps was also similar in wild-type and fmr1-/y mice (p = 0.1272, two way ANOVA; Figure 3C). Furthermore the lack of LTP cannot be explained by different spiking in response to the LTP protocol. The jitter i.e., the standard deviation of spike timing was 1.25 ± 0.38 SD and 1.308 ± 0.93 SD for wild-type and in fmr1-/y mice respectively (p = 0.8503, Student’s unpaired t-test). We also determined the excitatory postsynaptic potential-spike coupling (or E-S coupling) to directly evaluate how synaptic excitation is integrated to generate an action potential in wild-type and fmr1-/y littermates (Thomazeau et al., 2014). We found that the E-S coupling was similar in wild-type and in fmr1-/y mice (p = 0.1488, two way ANOVA, Figure 3D). We conclude that the lack of FMRP in fmr1-/y mice has no major effect on excitatory synaptic integration in accumbens MSNs. More generally, the data indicate that the lack of FMRP expression did not affect on the intrinsic properties of accumbens MSNs.

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