Functional and structural deficits at accumbens synapses in a mouse model of Fragile X

International audienceFragile 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

Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome

Fragile X syndrome, the most commonly known genetic cause of autism, is due to loss of the fragile X mental retardation protein, which regulates signal transduction at metabotropic glutamate receptor-5 in the brain. Fragile X mental retardation protein deletion in mice enhances metabotropic glutamate receptor-5-dependent long-term depression in the hippocampus and cerebellum. Here we show that a distinct type of metabotropic glutamate receptor-5-dependent long-term depression at excitatory synapses of the ventral striatum and prefrontal cortex, which is mediated by the endocannabinoid 2-arachidonoyl-sn-glycerol, is absent in fragile X mental retardation protein-null mice. In these mutants, the macromolecular complex that links metabotropic glutamate receptor-5 to the 2-arachidonoyl-sn-glycerolproducing enzyme, diacylglycerol lipase-α (endocannabinoid signalosome), is disrupted and metabotropic glutamate receptor-5-dependent 2-arachidonoyl-sn-glycerol formation is compromised. These changes are accompanied by impaired endocannabinoid-dependent long-term depression. Pharmacological enhancement of 2-arachidonoyl-sn-glycerol signalling normalizes this synaptic defect and corrects behavioural abnormalities in fragile X mental retardation protein-deficient mice. The results identify the endocannabinoid signalosome as

Influence of Different Envelope Maskers on Signal Recognition and Neuronal Representation in the Auditory System of a Grasshopper

Background: Animals that communicate by sound face the problem that the signals arriving at the receiver often are degraded and masked by noise. Frequency filters in the receiver’s auditory system may improve the signal-to-noise ratio (SNR) by excluding parts of the spectrum which are not occupied by the species-specific signals. This solution, however, is hardly amenable to species that produce broad band signals or have ears with broad frequency tuning. In mammals auditory filters exist that work in the temporal domain of amplitude modulations (AM). Do insects also use this type of filtering? Principal Findings: Combining behavioural and neurophysiological experiments we investigated whether AM filters may improve the recognition of masked communication signals in grasshoppers. The AM pattern of the sound, its envelope, is crucial for signal recognition in these animals. We degraded the species-specific song by adding random fluctuations to its envelope. Six noise bands were used that differed in their overlap with the spectral content of the song envelope. If AM filters contribute to reduced masking, signal recognition should depend on the degree of overlap between the song envelope spectrum and the noise spectra. Contrary to this prediction, the resistance against signal degradation was the same for five of six masker bands. Most remarkably, the band with the strongest frequency overlap to the natural song envelope (0–100 Hz) impaired acceptance of degraded signals the least. To assess the noise filter capacities of singl

Neuronal precision and the limits for acoustic signal recognition in a small neuronal network

Recognition of acoustic signals may be impeded by two factors: extrinsic noise, which degrades sounds before they arrive at the receiver’s ears, and intrinsic neuronal noise, which reveals itself in the trial-to-trial variability of the responses to identical sounds. Here we analyzed how these two noise sources affect the recognition of acoustic signals from potential mates in grasshoppers. By progressively corrupting the envelope of a female song, we determined the critical degradation level at which males failed to recognize a courtship call in behavioral experiments. Using the same stimuli, we recorded intracellularly from auditory neurons at three different processing levels, and quantified the corresponding changes in spike train patterns by a spike train metric, which assigns a distance between spike trains. Unexpectedly, for most neurons, intrinsic variability accounted for the main part of the metric distance between spike trains, even at the strongest degradation levels. At consecutive levels of processing, intrinsic variability increased, while the sensitivity to external noise decreased. We followed two approaches to determine critical degradation levels from spike train dissimilarities, and compared the results with the limits of signal recognition measured in behaving animals

Neuronale Variabilität und die Grenzen der Signalerkennung

Ziel der vorliegenden Arbeit war es, die Auswirkungen von externen Störquellen und intrinsischer Variabilität auf die Verarbeitung und Erkennung von akustischen Signalen am Modellsystem der Feldheuschrecke Chorthippus biguttulus zu untersuchen. Damit sowohl die Gesangserkennung am sich verhaltenden Tier als auch die dieser Erkennung zugrunde liegende neuronale Verarbeitung untersucht werden konnte, wurde ein Weibchengesang verwendet, dessen zeitliches Muster durch zufällige Amplitudenmodulationen gestört wurde. Durch die Degradation mit verschiedenen Frequenzbändern konnte überprüft werden, ob bestimmte Modulationsfrequenzen die Signalerkennung stärker beeinflussen als andere. Mit zunehmender Störung der Gesangsstruktur kam es in den Verhaltenstests an Männchen zu einer Abnahme der Erkennungsleistung. Die Stärke der tolerierten Degradation war dabei in der Regel nicht unterschiedlich für die getesteten Degradationsbänder. Die Unterschiede in den neuronalen Antworten, welche entweder durch die artifizielle extrinsische Degradation oder durch interne Fehler in der auditorischen Verarbeitung verursacht wurden, konnten durch eine Spiketrain-Metrik quantifiziert werden. Diese Analyse zeigte, dass die Auswirkung der extrinsischen Signaldegradation von den Rezeptoren über die lokalen Interneurone zu den aufsteigenden Interneuronen abnahm, während es zu einem signifikanten Anstieg der intrinsischen Variabilität kam. Die Stärke der Degradation war dabei erneut nicht unterschiedlich für die getesteten Degradationsbänder. Durch die Bestimmung von neurometrischen Schwellen konnten die Grenzen der Signalerkennung der Männchen mit der Rauschtoleranz der einzelnen auditorischen Neurone verglichen werden. Die kritischen Degradationsstufen, die so ermittelt werden konnten, stimmten teilweise erstaunlich gut überein. Somit sind die Grenzen der Signalerkennung durch die Analyse der Antwortkapazitäten der ersten drei Verarbeitungsstufen relativ gut erklärbar.The aim of this study was to investigate the effects of extrinsic and intrinsic noise sources on signal recognition and processing within the acoustic communication system of the grasshopper Chorthippus biguttulus. To test both - signal recognition of behaving animals and the underlying auditory processing mechanisms - a female song was used, whose temporal pattern was disturbed by random amplitude modulations. Due to the degradation with various modulation bands, it was possible to test if distinct modulation frequencies have more pronounced effects on signal recognition than others. Behavioural tests on males of Chorthippus biguttulus showed that progressive degradation of the song pattern induced a decrease in recognition performance. The strength of degradation tolerated generally was the same for different modulation bands. The differences between neuronal responses, which were either caused by the artificial extrinsic degradation or internal errors during auditory processing, could be quantified by a spiketrain metric. This analysis showed that the effect of extrinsic signal degradation was much more severe for receptors and local interneurons than for ascending interneurons, whereas there was a significant increase of intrinsic variability with higher levels of processing. The strength of the degradation was again not different for different modulation bands. Signal recognition could be compared with the noise tolerance of individual auditory neurons by determining neurometric thresholds. The average critical degradation levels, to some extend, matched the critical degradation level for behaviour. Thus, by means of analysing the response capacities of neurons from the first three levels of auditory processing, the limits of signal detection are relatively well explained

Muscarinic M1 Receptor Modulation of Synaptic Plasticity in Nucleus Accumbens of Wild-Type and Fragile X Mice

International audienceWe investigated how metabotropic acetylcho-line receptors control excitatory synaptic plasticity in the mouse nucleus accumbens core. Pharmacological and genetic approaches revealed that M 1 mAChRs (muscarinic acetylcho-line receptors) trigger multiple and interacting forms of synaptic plasticity. As previously described in the dorsal striatum, moderate pharmacological activation of M 1 mAChR potentiated postsynaptic NMDARs. The M 1-potentiation of NMDAR masked a previously unknown coincident TRPV1-mediated long-term depression (LTD). In addition, strong pharmacological activation of M 1 mAChR induced canonical retrograde LTD, mediated by presynaptic CB1R. In the f mr1-/ y mouse model of Fragile X, we found that CB1R but not TRPV1 M 1-LTD was impaired. Finally, pharmacological blockade of the degradation of anandamide and 2-arachidonylglycerol, the two principal endocannabinoids restored f mr1-/y LTD to wild-type levels. These findings shed new light on the complex influence of acetylcholine on excitatory synapses in the nucleus accumbens core and identify new substrates of the synaptic deficits of Fragile X

The influence of different envelope maskers on signal recognition.

<p>A) Turning response of one male tested with four different degradation bands. The abscissa shows the degradation levels in dB, ‘orig’ indicates the original song; ‘n’ indicates pure noise. The ordinate shows the percentage of turning responses. For each phonotaxis curve a behavioural critical degradation level (bCDL) was interpolated at the intersection of each phonotaxis-curve with the 50% response level. B) Cumulative percentage of bCDLs for five different bands of envelope degradation. The ordinate shows the cumulative bCDLs [in %] as a function of signal degradation (abscissa). C) The distribution of bCDLs for five of six frequency bands tested. Boxes cover the interquartile ranges, whiskers the range from the 10th to the 90th percentile. Points indicate the outliers The medians bCDLs of these bands were between-3 dB and 0 dB. 0–1000 Hz: median = −2 dB, N = 59; 0–1000 Hz notch: median = −1.2 dB N = 34, 100–500 Hz: median = −2.1 dB, N = 40, 200–750 Hz: median = −0.7 dB, N = 23; 100–200 Hz: median = −2.5 dB, N = 19.</p

The influence of the 0–100 Hz envelope masker on signal recognition.

<p>A) Phonotaxis response (ordinate) of seven males as a function of degradation level (abscissa) B) Attractiveness for each degradation level (abscissa) measured as the proportion of animals that responded in more than 50% of the trials (ordinate). Numbers within the bars indicate the median response probabilities. Altogether 20 males were tested, the sample sizes for the individual degradation levels were: −9 dB: N = 12, −6 dB: N = 9, −3 dB: N = 14, 0 dB: N = 12, 3 dB: N = 14, 6 dB: N = 12; 9 dB: N = 18. The pure noise (n) was tested on a different set of animals; N = 23. Asterisks mark significant differences between the original song and degraded songs (Fisher's exact test with Yates and Bonferroni-Holm correction). C) The upper and the middle panel show the oscillograms of the original female song degraded with 0–100 Hz at 6 and 9 dB respectively. The lower panel illustrates the degradation with 100–200 Hz at 9 dB degradation level.</p

Model songs used for behavioural and neurophysiological tests.

<p>A) The upper panel shows the oscillogram of the original female song which contained 12 similar syllables (S) of 80 ms length separated by pauses (P) of around 20 ms. The lower panel shows the enlargement of two syllables. Each syllable consisted of 6 sound pulses B) Amplitude spectrum of the envelope of the original female song. The frequency ranges of the different bands of envelope degradation, which were used both in behavioural experiments and intracellular recordings are indicated with coloured, horizontal bars. C) The envelopes of two song syllables before (dotted black line) and after adding envelope noise at 0 dB NSR (colored line).</p