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Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome.

ABSTRACT: Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified. Here, we identified collapsing response mediator protein (CRMP) mRNA as a target of FMRP. Knockdown of pan-neuronal CRMP expression ameliorated the circadian defects and abnormal axonal structures of clock neurons (ventral lateral neurons) in dfmr1 mutant flies. Furthermore, specific reduction of CRMP in the downstream output insulin-producing cells attenuated the aberrant circadian behaviors. Molecular analyses revealed that FMRP binds with CRMP mRNA and negatively regulates its translation. Our results indicate that CRMP is an FMRP target and establish an essential role for CRMP in the circadian output in FXS Drosophila.

SUBMITTER: Zhao J

PROVIDER: S-EPMC8275672 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome.

Zhao Juan J Xue Jin J Zhu Tengfei T He Hua H Kang Huaixing H Jiang Xuan X Huang Wen W Duan Ranhui R

Neuroscience bulletin 20210415 7

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, resulting from the lack of functional fragile X mental retardation protein (FMRP), an mRNA binding protein mainly serving as a translational regulator. Loss of FMRP leads to dysregulation of target mRNAs. The Drosophila model of FXS show an abnormal circadian rhythm with disruption of the output pathway downstream of the clock network. Yet the FMRP targets involved in circadian regulation have not been identified ...[more]

PMID: 33856646

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Project description:Fragile X syndrome is the most common inherited intellectual disability and monogenic cause of autism spectrum disorder. Expressive language deficits, especially in speech production, are nearly ubiquitous among individuals with fragile X, but understanding of the neurological bases for these deficits remains limited. Speech production depends on feedforward control and the synchronization of neural oscillations between speech-related areas of frontal cortex and auditory areas of temporal cortex. Interaction in this circuitry allows the corollary discharge of intended speech generated from an efference copy of speech commands to be compared against actual speech sounds, which is critical for making adaptive adjustments to optimize future speech. We aimed to determine whether alterations in coherence between frontal and temporal cortices prior to speech production are present in individuals with fragile X and whether they relate to expressive language dysfunction. Twenty-one participants with full-mutation fragile X syndrome (aged 7-55 years, eight females) and 20 healthy controls (matched on age and sex) completed a talk/listen paradigm during high-density EEG recordings. During the talk task, participants repeated pronounced short vocalizations of 'Ah' every 1-2 s for a total of 180 s. During the listen task, participants passively listened to their recordings from the talk task. We compared pre-speech event-related potential activity, N1 suppression to speech sounds, single trial gamma power and fronto-temporal coherence between groups during these tasks and examined their relation to performance during a naturalistic language task. Prior to speech production, fragile X participants showed reduced pre-speech negativity, reduced fronto-temporal connectivity and greater frontal gamma power compared to controls. N1 suppression during self-generated speech did not differ between groups. Reduced pre-speech activity and increased frontal gamma power prior to speech production were related to less intelligible speech as well as broader social communication deficits in fragile X syndrome. Our findings indicate that coordinated pre-speech activity between frontal and temporal cortices is disrupted in individuals with fragile X in a clinically relevant way and represents a mechanism contributing to prominent speech production problems in the disorder.

Project description:BackgroundFragile X syndrome (FXS), the most common genetic cause of autism spectrum disorder and intellectual disability, is caused by the lack of fragile X mental retardation protein (FMRP) expression. FMRP is an mRNA binding protein with functions in mRNA transport, localization, and translational control. In Fmr1 knockout mice, dysregulated translation has been linked to pathophysiology, including abnormal synaptic function and dendritic morphology, and autistic-like behavioral phenotypes. The role of FMRP in morphology and function of excitatory neurons has been well studied in mice lacking Fmr1, but the impact of Fmr1 deletion on inhibitory neurons remains less characterized. Moreover, the contribution of FMRP in different cell types to FXS pathophysiology is not well defined. We sought to characterize whether FMRP loss in parvalbumin or somatostatin-expressing neurons results in FXS-like deficits in mice.MethodsWe used Cre-lox recombinase technology to generate two lines of conditional knockout mice lacking FMRP in either parvalbumin or somatostatin-expressing cells and carried out a battery of behavioral tests to assess motor function, anxiety, repetitive, stereotypic, social behaviors, and learning and memory. In addition, we used fluorescent non-canonical amino acid tagging along with immunostaining to determine whether de novo protein synthesis is dysregulated in parvalbumin or somatostatin-expressing neurons.ResultsDe novo protein synthesis was elevated in hippocampal parvalbumin and somatostatin-expressing inhibitory neurons in Fmr1 knockout mice. Cell type-specific deletion of Fmr1 in parvalbumin-expressing neurons resulted in anxiety-like behavior, impaired social behavior, and dysregulated de novo protein synthesis. In contrast, deletion of Fmr1 in somatostatin-expressing neurons did not result in behavioral abnormalities and did not significantly impact de novo protein synthesis. This is the first report of how loss of FMRP in two specific subtypes of inhibitory neurons is associated with distinct FXS-like abnormalities.LimitationsThe mouse models we generated are limited by whole body knockout of FMRP in parvalbumin or somatostatin-expressing cells and further studies are needed to establish a causal relationship between cellular deficits and FXS-like behaviors.ConclusionsOur findings indicate a cell type-specific role for FMRP in parvalbumin-expressing neurons in regulating distinct behavioral features associated with FXS.

Project description:UnlabelledFragile X syndrome (FXS) is a neurodevelopmental disease. It is one of the leading monogenic causes of intellectual disability among boys with most also displaying autism spectrum disorder traits. Here we investigated the role of NMDA receptors on mGluR-dependent long-term depression (mGluR-LTD), a key biomarker in the disease, at four different developmental stages. First, we applied the mGluR agonist 3,5-dihydroxyphenylglycine in the absence or presence of the NMDAR blocker, APV, hereby unmasking the NMDAR component in this process. As expected, in the presence of APV, we found more LTD in the mouse KO than in WT. This, however, was only observed in the p30-60 age group. At all other age groups tested, mGluR-LTD was almost identical between KO and WT. Interestingly, at p60, in the absence of APV, no or very little LTD was found in KO that was completely restored by application of APV. This suggests that the underlying cause of the enhanced mGluR-LTD in KO (at p30) is caused by dysregulated NMDAR signaling. To investigate this further, we next used NMDAR-subunit-specific antagonists. Inhibition of GluN2B, but not GluN2A, blocked mGluR-LTD only in WT. This was in contrast in the KO where blocking GluN2B rescued mGluR-LTD, suggesting GluN2B-containing NMDARs in the KO are hyperactive. Thus, these findings suggest strong involvement of GluN2B-containing-NMDARs in the pathophysiology of FXS and highlight a potential path for treatment for the disease.Significance statementThere is currently no cure for fragile X, although medications targeting specific FXS symptoms do exist. The FXS animal model, the Fmr1 knock-out mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD) leading to several clinical trials of mGluR5 inhibitors/modulators, yet all have failed. In addition, surprisingly little information exists about the possible role of other ion channels/receptors, including NMDA receptors (NMDAR), in mGluR-LTD. Here we focus on NMDARs and their regulation of mGluR-mediated LTD at different developmental stages using several different NMDAR blockers/antagonists. Our findings suggest dysregulated NMDARs in the pathophysiology of FXS leading to altered mGluR-mediated LTD. Together, these data will help to develop new drug candidates that could lead to reversal of the FXS phenotype.

Dataset Information

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome.

Publications

Dysregulated CRMP Mediates Circadian Deficits in a Drosophila Model of Fragile X Syndrome.

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