Biology subjects

Fransen, E.

Publications and source records attributed to Fransen, E..

6 recordsLinked to original sources

bioRxiv2026

The Female Side of Autism: Sexual Dichotomies impacting the Helsmoortel-Van der Aa syndrome pathology.

Background: Helsmoortel-Van der Aa syndrome, caused by pathogenic variants in ADNP, is characterised by substantial clinical heterogeneity, but how biological sex influences disease biology and treatment response remains an emerging area of investigation. Here, we investigated whether sex modifies the behavioural and molecular consequences of Adnp deficiency, the response to the investigational drug candidate davunetide (NAP), and the clinical phenotype of Helsmoortel-Van der Aa syndrome. Methods: We studied male and female Adnp heterozygous mice harbouring the p.Leu822Hisfs*6 variant and sex-matched wild-type littermates using continuous 24-h behavioural phenotyping, hippocampal genome-wide DNA methylation and bulk RNA sequencing. NAP effects on behaviour, hippocampal ADNP protein abundance, and epi-transcriptomic responses were assessed using genotype-by-treatment models. Four Core Genotypes mice were assessed to distinguish sex-chromosome and gonadal contributions to hippocampal Adnp transcript expression, and reproductive-tissue transcriptomes were analysed in Adnp mice to unravel a possible endocrine component of the disease. Findings were compared with clinical and developmental data from 129 individuals with Helsmoortel-Van der Aa syndrome. Findings: Adnp deficiency produced a shared overall behavioural phenotype in male and female mice, but through distinct patterns of behavioural disruption, indicating that sex modifies the implementation rather than the magnitude of the phenotype. This distinction was also evident at the molecular level: hippocampal DNA methylation was predominantly determined by genotype and showed convergence between sexes, whereas transcriptional responses diverged, with mitochondrial pathways predominating in males and chromatin, RNA processing, and cell-cycle pathways in females. NAP partially shifted behavioural abnormalities towards the wild-type state in both sexes and increased hippocampal ADNP protein abundance in heterozygous mice, without reversing the underlying methylation phenotype. Its transcriptional effects were markedly broader in males, indicating a sex-dependent molecular response to treatment. In reproductive tissues, Adnp deficiency was associated with convergent alterations in steroid hormone biosynthesis, despite no evidence for direct regulation of hippocampal Adnp expression by sex-chromosome complement or gonadal hormonal state. By contrast, sex was not associated with robust differences across the clinical and developmental features assessed in 129 individuals with Helsmoortel-Van der Aa syndrome after correction for multiple testing. Interpretation: Biological sex modifies how Adnp deficiency is expressed at behavioural and molecular levels, but these differences do not necessarily define distinct clinical phenotypes. The convergence of the methylation response alongside greater divergence in transcriptional and behavioural responses identifies sex as a modifier of disease biology rather than a determinant of the core phenotype. The sex-dependent response to NAP further indicates that biological sex may influence pharmacological responses even when treatment-associated behavioural improvement is observed in both sexes. These findings support consideration of biological sex as a prespecified variable in preclinical and clinical studies of Helsmoortel-Van der Aa syndrome and suggest that systematic investigation of sex-dependent biology may also be relevant to therapeutic development across rare diseases. Keywords: Helsmoortel-Van der Aa syndrome (HVDAS), Activity-Dependent Neuroprotective Protein (ADNP), autism spectrum disorder, intellectual disability, sex, mouse model, behaviour.

genetics↗

bioRxiv2025

Shapes of synaptic protein distributions distinguish brain architectures

Neuronal activity is the result of the orchestrated actions of multitudes of synapses, acting and evolving not as individuals, but as populations. We therefore collected, for millions of synapses, a functionally relevant proxy for their strengths. Namely, we measured postsynaptic protein content by deploying a fluorescent PSD95 variant. Then we summarized, by statistical moments, the shapes of the distributions of protein contents, over local synaptic populations. In this way we explored the hypothesis that such collective properties inform on brain architectures. Our measurements cover complete parasagittal sections of the mouse brain, in animals one week to 18 months old. We identified a hierarchical organization of regions along the anterior-posterior axis, with three main clusters of divergent synaptic population shapes. One includes telencephalic regions, one is centered in the midbrain and hindbrain, and one comprises mainly the thalamus and the cerebellum. The structure emerging from our approach aligns with discoveries in studies of regional patterns of cellular gene expressions. Our results suggest that synaptic populations are dynamically regulated over the lifespan. Regions which at three months of age have thinner tails largely conserve their distribution shapes later in life, whereas heavy tails in other regions strikingly grow ever more so.

neuroscience↗

bioRxiv2023

Sleep maintains excitatory synapse diversity in the cortex and hippocampus

How sleep deprivation affects cognition remains elusive. Synaptome mapping of excitatory synapses in 125 regions of the mouse brain revealed that sleep deprivation selectively reduces synapse diversity in the cortex and hippocampus. Sleep deprivation targeted specific types and subtypes of excitatory synapses while maintaining total synapse density. Altered synaptic responses to neural oscillations in a computational model suggest that sleep prevents cognitive impairments by maintaining normal brain synaptome architecture.

neuroscience↗

bioRxiv2021

Developmental resilience of synaptome architecture

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence occur in many disorders1-10, suggesting that brain circuits possess an intrinsic capacity to repair themselves. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model11. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the postnatal expansion of synapse diversity and acquisition of normal synaptome architecture were delayed in all brain regions, interfering with network and cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synaptome architecture to its normal developmental trajectory. Synapse subtypes with high rates of protein turnover mediated these events. These results show synaptome remodelling confers resilience to neurodevelopmental disorders.

neuroscience↗

bioRxiv2021

A brain atlas of synapse protein lifetime across the mouse lifespan.

Protein turnover is required for synapse maintenance and remodelling and may impact memory duration. We quantified the lifetime of postsynaptic protein PSD95 in individual excitatory synapses across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of protein lifetimes that may extend from a few hours to several months, with distinct spatial distributions in dendrites, neuron types and brain regions. Short protein lifetime (SPL) synapses are enriched in developing animals and in regions controlling innate behaviors, whereas long protein lifetime (LPL) synapses accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. The protein lifetime synaptome architecture is disrupted in an autism model, with synapse protein lifetime increased throughout the brain. These findings add a further layer to synapse diversity in the brain and enrich prevailing concepts in behavior, development, ageing and brain repair.

neuroscience↗

bioRxiv2019

A lifespan program of mouse synaptome architecture

How synapses change molecularly during the lifespan and across all brain circuits is unknown. We analyzed the protein composition of billions of individual synapses from birth to old age on a brain-wide scale in the mouse, revealing a program of changes in the lifespan synaptome architecture spanning individual dendrites to the systems level. Three major phases were uncovered, corresponding to human childhood, adulthood and old age. An arching trajectory of synaptome architecture drives the differentiation and specialization of brain regions to a peak in young adults before dedifferentiation returns the brain to a juvenile state. This trajectory underscores changing network organization and hippocampal physiology that may account for lifespan transitions in intellectual ability and memory, and the onset of behavioral disorders. One sentence summaryThe synaptome architecture of the mouse brain undergoes continuous changes that organize brain circuitry across the lifespan.

neuroscience↗