Neuroscience
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Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD; however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). ⋯ Notably, a 2-day paradigm of enriched whisker stimulation rescued both number and configuration of excitatory synapses in Cdkl5-KO mice, restored cortical activity and normalized behavioral responses to wild-type mice levels. Our findings disclose a novel and unsuspected role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli. This article is part of a Special Issue entitled: Animal Models of Neurodevelopmental Disorders.
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Neurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile X syndrome, autism spectrum disorders and Down syndrome, among others. They are characterized by limitations in adaptive and social behaviors, as well as intellectual disability (ID). Whole-exome and whole-genome sequencing studies have highlighted a large number of NDD/ID risk genes. ⋯ The fruit fly, Drosophila melanogaster, is an ideal model to study NDDs, with highly tractable genetics, combined with simple behavioral and circuit assays, permitting rapid medium-throughput screening of NDD/ID risk genes. Here, we review studies where the use of well-established assays to study mechanisms of learning and memory in Drosophila has permitted insights into molecular mechanisms underlying IDs. We discuss how technologies in the fly model, combined with a high degree of molecular and physiological conservation between flies and mammals, highlight the Drosophila system as an ideal model to study neurodevelopmental disorders, from genetics to behavior.
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Autism Spectrum Disorders (ASD) are characterized by heterogeneity both in their presentation and their genetic aetiology. In order to discover points of convergence common to different cases of ASD, attempts were made to identify the biological pathways genes associated with ASD contribute to. Many of these genes were found to play a role in neuronal and synaptic development and function. ⋯ This overlap in the phenotypes associated with these mouse models likely arises from the molecular interaction between the protein products of FMR1, CYFIP1, and NLG3. A number of other proteins linked to ASD are also likely to participate in these pathways, resulting in further downstream effects. Overall, a synaptic pathway centered around FMR1, CYFIP1, and NLG3 is likely to contribute to the phenotypes associated with structural and physiological plasticity characteristic of ASD.
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Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. ⋯ Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context.
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Autism is a complex spectrum of disorders characterized by core behavioral deficits in social communicative behavior, which are also required for comprehensive analysis of preclinical mouse models. As animal models of the core behavioral deficits in autism, two inbred mouse strains, BTBR T+ Itpr3tf/J (BTBR) and BALB/cJ (BALB), were compared with the standard social strain, C57BL/6J (B6), regarding a variety of behavioral factors underlying social communicative interactions, including olfactory and tactile sensory processes, social recognition abilities and behavioral expression strategies. Although both female BTBR and BALB mice can express social recognition and approach behavior depending on the stimuli they encounter, the available sensory modalities, along with modulation of the serotonergic system, differ between the two strains. ⋯ Systemic injection of the serotonin (5-HT1A) agonist buspirone has little effect on these social deficits, suggesting a congenitally degraded serotonergic system in BALB mice. In contrast, BTBR mice exhibit impaired body coordination and social motivation-modified olfactory signals, which are relevant to a reduced social approach. A systemic injection of the 5-HT1A agonist restored these social deficits in BTBR mice, indicating that a downregulated serotonergic system is involved in the social deficits exhibited by BTBR mice.