Jul 2026· Behavioral and Brain Functions· 0 citations
Medicine
TL;DR
It is indicated that postnatal Hoxa5 deficiency selectively enhances stereotyped behaviors without broadly affecting motor or social functions, which supports a model in which HOXA5 acts as a modulator of postnatal precerebellar circuit connectivity and/or function, with subtle behavioral consequences that require further research in specific genetic or environmental contexts.
Abstract
Hoxa5 encodes a transcription factor essential for embryonic patterning and organogenesis, with sustained expression in hindbrain precerebellar nuclei during postnatal development. Given prior evidence implicating HOXA5 in synaptogenesis and early postnatal circuit maturation, we investigated whether its inactivation during this critical developmental window contributes to neurodevelopmental disorder (NDD)-related phenotypes. Using previously generated transcriptomic data, we identified multiple deregulated genes classified as autism spectrum disorder (ASD) risk genes in the SFARI database, several of which are associated with a cerebellar phenotype in mice. We then performed a comprehensive behavioral assessment across motor, social, stereotypical, anxiety-related, and attentional domains in a postnatal inactivation mouse model (Hoxa5-cKO). Motor coordination, learning, gait, and sensorimotor functions were preserved. Social behavior assays yielded no consistent genotype-dependent effects, although results were sensitive to analytical methods and cohort variability. In contrast, Hoxa5-cKO mice exhibited increased stereotypical behaviors, including elevated scratching and marble burying, in the absence of anxiety- or locomotion-related confounds. Importantly, interpretation of social and cognitive phenotypes was impacted by well-known constraints of behavioral neuroscience. We discuss these downfalls and propose additional guidelines. Altogether, our findings indicate that postnatal Hoxa5 deficiency selectively enhances stereotyped behaviors without broadly affecting motor or social functions. The data support a model in which HOXA5 acts as a modulator of postnatal precerebellar circuit connectivity and/or function, with subtle behavioral consequences that require further research in specific genetic or environmental contexts.
Behavioral dysfunction is a common characteristic of many neurodevelopmental and mental health disorders. While the causes of these disorders vary, aberrant behaviors may arise from alterations in transcriptional regulation during early neural development. Because transcription factors (TFs) often belong to families of closely related members, disruption of a single TF may indirectly influence the functionality of other family members. Consequently, mutations in TFs within the same family may lead to overlapping, yet distinct, phenotypes. This feature of TF function has important implications for understanding behavioral phenotypes, but detailed analyses across a single TF family are still lacking. In this study, we present a comprehensive behavioral analysis of adult zebrafish harboring mutations in individual members of the TALE and Hox TF families, that are essential for nervous system development. Using a battery of validated behavioral assays, we uncover elevated stress responses among all TF mutant lines, as well as TF-specific dysregulation in social interaction, locomotion, and endurance. The shared behavioral abnormalities across mutants suggest TF family members converge on core developmental pathways for stress-related behavioral regulation, while mutation-specific phenotypes indicate unique roles for individual TFs in fine-tuning neural function. Our findings provide a systematic behavioral characterization of TALE and Hox mutants in a vertebrate model and provide a framework for understanding how genetic variation within TF families may differentially contribute to vulnerability for neurodevelopmental and mental health disorders.
Austin M. Adkins, K. Glowinski, Yong-Il Kim et al.· Behavior Genetics· 0 citations
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with an unclear pathogenesis. Growing evidence implicates excitatory/inhibitory (E/I) imbalance in ASD pathophysiology, prompting an investigation into gamma-aminobutyric acid (GABA)-mediated inhibitory transmission. The transcription factor Paired Box 2 (Pax2), essential for GABAergic interneuron specification, participates in the regulation of neural developmental processes. Our previous work demonstrated an E/I imbalance in the neurotransmitter system and reduced GABAARα2-positive neurons in the prefrontal cortex (PFC) of Pax2 neuron-specific deletion mice, though the internal molecular regulatory mechanism remained elusive. In this study, we generated GABAergic neuron-specific Pax2 knockdown mice via injection of AAV-shPax2 virus and comprehensively evaluated ASD-related behaviors, revealing autism-like behaviors, such as impaired social novelty and repetitive behaviors. Molecular analysis revealed upregulation of Tcf7l2, a key downstream mediator of the Wnt/β-catenin signaling pathway. Functional assessment confirmed hyperactivation of the Wnt/β-catenin signaling pathway in GABAergic neuron Pax2 knockdown mice. Notably, pharmacological intervention with esculetin, an inhibitor of the Wnt/β-catenin pathway, ameliorated the observed autism-like behaviors. These findings establish a pathogenic axis wherein GABAergic neuron-specific Pax2 deficiency induces hyperactivation of the Wnt/β-catenin signaling pathway and disrupts E/I balance, ultimately driving autism-like behavioral phenotypes. Our results further identify inhibition of Wnt/β-catenin signaling as a promising therapeutic strategy for ASD.
Germline heterozygous TCF4 LOF, which models PTHS, does not appear to significantly affect the astrocyte lineage at the cell population level, and germline heterozygous Tcf4 LOF did not result in misallocation of ventrally derived astrocytes into the dorsal cortex.
Sarain Stump, Joseph F. Bohlen, BaDoi N. Phan et al.· Neuroglia· 0 citations
Cortical immature neurons (cINs) represent a unique population of prenatally generated, non-dividing neurons that maintain an immature phenotype, characterized by doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) expression, into adulthood. Unlike canonical adult neurogenesis involving continuous neuron generation from stem cell niches, cINs constitute a distinct form of structural plasticity termed “neurogenesis without division”. This review comprehensively examines the molecular markers, morphological diversity, developmental origins, and maturation trajectories of cINs across species. We highlight the striking inverse interspecies relationship between cIN abundance and canonical adult neurogenesis, reflecting distinct biophysical and structural shifts in neural plasticity mechanisms across mammalian lineages. Furthermore, we discuss factors modulating cIN phenotype, including neurotransmitter systems, stress, sensory experience, and aging. Clinical evidence implicating cIN alterations in temporal lobe epilepsy, traumatic brain injury, and stroke is evaluated, revealing potential roles in both pathological circuit remodeling and endogenous repair. Critical gaps remain regarding the molecular programs maintaining immaturity, differentiation triggers, and the functional consequences of circuit integration. Understanding cIN biology offers new perspectives on cortical plasticity and may inform therapeutic strategies targeting endogenous cellular reserves for brain repair.
V. Riga, V. Aniol, N. Gulyaeva· International Journal of Mol...· 0 citations
An autism model of frk‐knockout with an assessable behavior phenotype in zebrafish is established and key insights into cell proliferation and the influence of the cyp24a1/tp53 pathway‐regulated cell proliferation on frk‐knockout‐induced autism‐like behaviors are provided.
Autism spectrum disorder (ASD) is characterized by persistent deficits in social communication and the presence of restricted and repetitive behaviors. While ASD has a neurodevelopmental origin, it remains a lifelong condition, yet little is known about how its behavioral and neural features evolve across adulthood. Here, we investigated behavioral, synaptic, and structural alterations across the transition from early to mature adulthood in Cntnap2 knockout mice, a widely used model of ASD. Using a longitudinal behavioral approach combined with electrophysiological recordings and morphological analysis, we show that KO mice exhibit increased stereotyped and repetitive behaviors and reduced exploratory activity at both ages. However, detailed analysis of behavioral patterns revealed age-dependent differences, with early adult KO mice displaying increased behavioral persistence that later evolved into distinct patterns of behavioral sequences. These behavioral changes were associated with alterations in inhibitory synaptic transmission in the dorsolateral striatum (DLS), including changes in spontaneous inhibitory postsynaptic current (sIPSC) frequency and temporal structure. In parallel, mature adult KO mice showed structural remodeling of spiny projection neurons, characterized by increased distal dendritic arborization and age-dependent organization of dendritic spines. Together, our findings demonstrate that ASD-related alterations are not static but evolve across adulthood, revealing a multi-level reorganization of behavioral, synaptic, and structural features. These results highlight the importance of considering adulthood stages in ASD and provide new insights into the dynamic nature of the condition.
Mathieu Thabault, Cloé Fernandes-Gomes, Cloé Alcaraz et al.· Neurobiology of Disease· 0 citations