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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

NMDAR-dependent spike timing-dependent potentiation (LTP) in accumbens medium spiny neurons. (A) Schematic representation of the pre-post protocol used to induce LTP. After the presynaptic stimulation the postsynaptic cell was depolarized for 30 ms to elicit an action potential. The time delay between presynaptic stimulation and the elicited spike was set to 25 ms. (B) Representative experiment illustrating the induction of LTP. Inset shows EPSCS sampled during the 10 min baseline and 20 min after LTP induction respectively. (C) Representative experiment showing that LTP in WT mice was abolished by the application of the NMDAR-antagonist D-APV (50 μM). (D) Summary of LTP experiments with (white circles) and without D-APV (black circles). LTP was blocked by application of 50 μM D-APV (p = 0.0441 Mann-Whitney test).
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Figure 1: NMDAR-dependent spike timing-dependent potentiation (LTP) in accumbens medium spiny neurons. (A) Schematic representation of the pre-post protocol used to induce LTP. After the presynaptic stimulation the postsynaptic cell was depolarized for 30 ms to elicit an action potential. The time delay between presynaptic stimulation and the elicited spike was set to 25 ms. (B) Representative experiment illustrating the induction of LTP. Inset shows EPSCS sampled during the 10 min baseline and 20 min after LTP induction respectively. (C) Representative experiment showing that LTP in WT mice was abolished by the application of the NMDAR-antagonist D-APV (50 μM). (D) Summary of LTP experiments with (white circles) and without D-APV (black circles). LTP was blocked by application of 50 μM D-APV (p = 0.0441 Mann-Whitney test).

Mentions: Numerous forms of activity-dependent LTD are expressed by accumbens synapses (Robbe et al., 2002a,b,c; Grueter et al., 2010). Reports of LTP are less common (Pennartz et al., 1993; Kombian and Malenka, 1994; Schramm et al., 2002; Schotanus and Chergui, 2008a) and complicated by the poor reliability of the induction protocols (Robbe et al., 2002b; Ji and Martin, 2012). Spike-timing-dependent plasticity (STDP) is widely considered as a physiologically relevant paradigm to trigger synaptic plasticity at central synapses (Dan and Poo, 2004; Caporale and Dan, 2008). While STDP has been well described for excitatory synapses in the dorsal striatum (Shen et al., 2008; Fino and Venance, 2010; Paille et al., 2013), a reliable LTP inducing STDP protocol for the ventral striatum is still lacking (Ji and Martin, 2012). Therefore, we first systematically searched for a consistent STDP protocol for accumbens medium spiny neurons (MSN) in adult wild-type mice based on induction parameters published a priori (Fino et al., 2005). When presynaptic stimulation was followed by a 30 ms postsynaptic depolarization eliciting a spike (dt = 25 ms), we observed a strong potentiation of synaptic efficacy (p = 0.0134 Wilcoxon matched pairs signed rank test, Figures 1A,B). Typically, LTP depends on the activation of postsynaptic NMDAR (Markram et al., 1997; Dan and Poo, 2004; Nevian and Sakmann, 2006). Accordingly, we found that bath application of the specific NMDAR antagonist D-APV completely prevented LTP (p = 0.0441, Mann-Whitney test; Figures 1C,D). Together these experiments demonstrate that accumbens excitatory synapses can reliably express NMDAR-dependent LTP with induction parameters specific for this synapse type.


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)

NMDAR-dependent spike timing-dependent potentiation (LTP) in accumbens medium spiny neurons. (A) Schematic representation of the pre-post protocol used to induce LTP. After the presynaptic stimulation the postsynaptic cell was depolarized for 30 ms to elicit an action potential. The time delay between presynaptic stimulation and the elicited spike was set to 25 ms. (B) Representative experiment illustrating the induction of LTP. Inset shows EPSCS sampled during the 10 min baseline and 20 min after LTP induction respectively. (C) Representative experiment showing that LTP in WT mice was abolished by the application of the NMDAR-antagonist D-APV (50 μM). (D) Summary of LTP experiments with (white circles) and without D-APV (black circles). LTP was blocked by application of 50 μM D-APV (p = 0.0441 Mann-Whitney test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: NMDAR-dependent spike timing-dependent potentiation (LTP) in accumbens medium spiny neurons. (A) Schematic representation of the pre-post protocol used to induce LTP. After the presynaptic stimulation the postsynaptic cell was depolarized for 30 ms to elicit an action potential. The time delay between presynaptic stimulation and the elicited spike was set to 25 ms. (B) Representative experiment illustrating the induction of LTP. Inset shows EPSCS sampled during the 10 min baseline and 20 min after LTP induction respectively. (C) Representative experiment showing that LTP in WT mice was abolished by the application of the NMDAR-antagonist D-APV (50 μM). (D) Summary of LTP experiments with (white circles) and without D-APV (black circles). LTP was blocked by application of 50 μM D-APV (p = 0.0441 Mann-Whitney test).
Mentions: Numerous forms of activity-dependent LTD are expressed by accumbens synapses (Robbe et al., 2002a,b,c; Grueter et al., 2010). Reports of LTP are less common (Pennartz et al., 1993; Kombian and Malenka, 1994; Schramm et al., 2002; Schotanus and Chergui, 2008a) and complicated by the poor reliability of the induction protocols (Robbe et al., 2002b; Ji and Martin, 2012). Spike-timing-dependent plasticity (STDP) is widely considered as a physiologically relevant paradigm to trigger synaptic plasticity at central synapses (Dan and Poo, 2004; Caporale and Dan, 2008). While STDP has been well described for excitatory synapses in the dorsal striatum (Shen et al., 2008; Fino and Venance, 2010; Paille et al., 2013), a reliable LTP inducing STDP protocol for the ventral striatum is still lacking (Ji and Martin, 2012). Therefore, we first systematically searched for a consistent STDP protocol for accumbens medium spiny neurons (MSN) in adult wild-type mice based on induction parameters published a priori (Fino et al., 2005). When presynaptic stimulation was followed by a 30 ms postsynaptic depolarization eliciting a spike (dt = 25 ms), we observed a strong potentiation of synaptic efficacy (p = 0.0134 Wilcoxon matched pairs signed rank test, Figures 1A,B). Typically, LTP depends on the activation of postsynaptic NMDAR (Markram et al., 1997; Dan and Poo, 2004; Nevian and Sakmann, 2006). Accordingly, we found that bath application of the specific NMDAR antagonist D-APV completely prevented LTP (p = 0.0441, Mann-Whitney test; Figures 1C,D). Together these experiments demonstrate that accumbens excitatory synapses can reliably express NMDAR-dependent LTP with induction parameters specific for this synapse type.

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