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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

Glutamatergic transmission parameters in the nucleus accumbens of wild-type and fmr-/y mice. (A) Average field responses to electric stimulation of increasing intensity did not reveal a significant difference in synaptic excitability between the two genotypes. The overall excitability was not significantly different between the two genotypes (p = 0.1436, 2-way ANOVA, the number of animals tested differed between stimulation intensities n = 14–31, data not shown). (B) Example traces illustration the response to paired stimulations for a wild type (upper trace) and a fmr1-/y mouse (lower trace). The comparison of the median paired-pulse ratios for a stimulus interval of 50ms revealed no significant difference between the two genotypes (p = 0.4354, WT n = 21, fmr1-/y n = 16, students t-test). (C) Sample traces from accumbens MSN clamped at −70 mV from wild type and fmr1/y animals (scale bar: 50 ms, 20 pA). The cumulative probability distribution of AMPAR sEPSCs amplitudes revealed no differences between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black symbols; fmr1-/y n = 10, white symbols). (D) The cumulative probability distribution of AMPAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black circles; fmr1-/y n = 10, white circles). (E) Sample traces from accumbens MSN clamped at +40 mV from wild type and fmr1-/y animals (scale bar: 2 s, 50 pA). The cumulative probability distribution of NMDAR sEPSCs amplitudes revealed a significant difference between the two genotypes (Kolmogorov-Smirnov-test p < 0.0001); WT n = 9, black symbols; fmr1-/y n = 5 white symbols). (F) The cumulative probability distribution of NMDAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 9, black circles; fmr1-/y n = 5, white circles).
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Figure 4: Glutamatergic transmission parameters in the nucleus accumbens of wild-type and fmr-/y mice. (A) Average field responses to electric stimulation of increasing intensity did not reveal a significant difference in synaptic excitability between the two genotypes. The overall excitability was not significantly different between the two genotypes (p = 0.1436, 2-way ANOVA, the number of animals tested differed between stimulation intensities n = 14–31, data not shown). (B) Example traces illustration the response to paired stimulations for a wild type (upper trace) and a fmr1-/y mouse (lower trace). The comparison of the median paired-pulse ratios for a stimulus interval of 50ms revealed no significant difference between the two genotypes (p = 0.4354, WT n = 21, fmr1-/y n = 16, students t-test). (C) Sample traces from accumbens MSN clamped at −70 mV from wild type and fmr1/y animals (scale bar: 50 ms, 20 pA). The cumulative probability distribution of AMPAR sEPSCs amplitudes revealed no differences between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black symbols; fmr1-/y n = 10, white symbols). (D) The cumulative probability distribution of AMPAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black circles; fmr1-/y n = 10, white circles). (E) Sample traces from accumbens MSN clamped at +40 mV from wild type and fmr1-/y animals (scale bar: 2 s, 50 pA). The cumulative probability distribution of NMDAR sEPSCs amplitudes revealed a significant difference between the two genotypes (Kolmogorov-Smirnov-test p < 0.0001); WT n = 9, black symbols; fmr1-/y n = 5 white symbols). (F) The cumulative probability distribution of NMDAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 9, black circles; fmr1-/y n = 5, white circles).

Mentions: We next measured field EPSPs (fEPSP) of accumbens MSNs to build input-output profiles in the two genotypes. fEPSPs evoked by electrical stimulation showed a consistent profile distribution in response to increasing stimulation intensity across different slices and mice (Figure 4A). Furthermore, input-output curves from wild-type and fmr1-/y littermates were identical. The data show that the excitability of accumbens MSN synapses was unaltered (Figure 4A). Additionally, the paired pulse ratio, a form of short-term synaptic plasticity that depends on release probability of glutamate, was identical in both genotypes (Figure 4B). These data suggest that the lack of LTP is unlikely due to a reduction of the number of synapses recruited during the induction of synaptic plasticity in fmr1-/y accumbens synapses.


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)

Glutamatergic transmission parameters in the nucleus accumbens of wild-type and fmr-/y mice. (A) Average field responses to electric stimulation of increasing intensity did not reveal a significant difference in synaptic excitability between the two genotypes. The overall excitability was not significantly different between the two genotypes (p = 0.1436, 2-way ANOVA, the number of animals tested differed between stimulation intensities n = 14–31, data not shown). (B) Example traces illustration the response to paired stimulations for a wild type (upper trace) and a fmr1-/y mouse (lower trace). The comparison of the median paired-pulse ratios for a stimulus interval of 50ms revealed no significant difference between the two genotypes (p = 0.4354, WT n = 21, fmr1-/y n = 16, students t-test). (C) Sample traces from accumbens MSN clamped at −70 mV from wild type and fmr1/y animals (scale bar: 50 ms, 20 pA). The cumulative probability distribution of AMPAR sEPSCs amplitudes revealed no differences between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black symbols; fmr1-/y n = 10, white symbols). (D) The cumulative probability distribution of AMPAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black circles; fmr1-/y n = 10, white circles). (E) Sample traces from accumbens MSN clamped at +40 mV from wild type and fmr1-/y animals (scale bar: 2 s, 50 pA). The cumulative probability distribution of NMDAR sEPSCs amplitudes revealed a significant difference between the two genotypes (Kolmogorov-Smirnov-test p < 0.0001); WT n = 9, black symbols; fmr1-/y n = 5 white symbols). (F) The cumulative probability distribution of NMDAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 9, black circles; fmr1-/y n = 5, white circles).
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Related In: Results  -  Collection

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Figure 4: Glutamatergic transmission parameters in the nucleus accumbens of wild-type and fmr-/y mice. (A) Average field responses to electric stimulation of increasing intensity did not reveal a significant difference in synaptic excitability between the two genotypes. The overall excitability was not significantly different between the two genotypes (p = 0.1436, 2-way ANOVA, the number of animals tested differed between stimulation intensities n = 14–31, data not shown). (B) Example traces illustration the response to paired stimulations for a wild type (upper trace) and a fmr1-/y mouse (lower trace). The comparison of the median paired-pulse ratios for a stimulus interval of 50ms revealed no significant difference between the two genotypes (p = 0.4354, WT n = 21, fmr1-/y n = 16, students t-test). (C) Sample traces from accumbens MSN clamped at −70 mV from wild type and fmr1/y animals (scale bar: 50 ms, 20 pA). The cumulative probability distribution of AMPAR sEPSCs amplitudes revealed no differences between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black symbols; fmr1-/y n = 10, white symbols). (D) The cumulative probability distribution of AMPAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 14, black circles; fmr1-/y n = 10, white circles). (E) Sample traces from accumbens MSN clamped at +40 mV from wild type and fmr1-/y animals (scale bar: 2 s, 50 pA). The cumulative probability distribution of NMDAR sEPSCs amplitudes revealed a significant difference between the two genotypes (Kolmogorov-Smirnov-test p < 0.0001); WT n = 9, black symbols; fmr1-/y n = 5 white symbols). (F) The cumulative probability distribution of NMDAR sEPSCs inter-event-intervals revealed no differences in spontaneous synaptic transmission between the two genotypes (Kolmogorov-Smirnov-test; WT n = 9, black circles; fmr1-/y n = 5, white circles).
Mentions: We next measured field EPSPs (fEPSP) of accumbens MSNs to build input-output profiles in the two genotypes. fEPSPs evoked by electrical stimulation showed a consistent profile distribution in response to increasing stimulation intensity across different slices and mice (Figure 4A). Furthermore, input-output curves from wild-type and fmr1-/y littermates were identical. The data show that the excitability of accumbens MSN synapses was unaltered (Figure 4A). Additionally, the paired pulse ratio, a form of short-term synaptic plasticity that depends on release probability of glutamate, was identical in both genotypes (Figure 4B). These data suggest that the lack of LTP is unlikely due to a reduction of the number of synapses recruited during the induction of synaptic plasticity in fmr1-/y accumbens synapses.

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