Biology subjects

Zmorzynska, J.

Publications and source records attributed to Zmorzynska, J..

4 recordsLinked to original sources

bioRxiv2026

Loss of Brg1 promotes seizure development via GABAergic system disruption

The Brahma-related gene 1 (BRG1) encodes the catalytic subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex and plays an important role in brain development. Variants in SWI/SNF components are often found in patients with epilepsy, but it is still unclear how loss of BRG1 function contributes to seizure development. In this study, we analyzed the role of Brg1 in seizure susceptibility using zebrafish models with both pharmacological inhibition or genetic reduction of Brg1. Reduced Brg1 function caused seizure-like behavior and increased neuronal activity in larvae, while basic locomotor activity was preserved. Further analyses showed reduced expression of several GABAergic system markers. In contrast, glutamatergic markers did not show major changes. These results point to a selective impairment of inhibitory signaling. When GABA levels were increased pharmacologically, seizure-like behavior was reduced. This suggests that loss of inhibitory transmission plays an important role in the observed hyperexcitability. Unbiased omics analyses also identified changes in proteins associated with vitamin B6 binding. Treatment with active vitamin B6 reduced seizure-like behavior in larvae with reduced Brg1 function. Taken together, these results indicate that Brg1 is required for proper inhibitory neurotransmission and that partial loss of Brg1 function increases seizure susceptibility. These findings may help to better understand why mutations in chromatin remodeling genes are often associated with epilepsy and could support future studies on targeted modulation of inhibitory signaling in these conditions. Significance StatementChromatin remodeling genes are often mutated in patients with epilepsy, but it is still unclear how these mutations lead to seizures. In this study, we show that reduced function of the chromatin remodeler Brg1 affects inhibitory neurotransmission by impairing the GABAergic system. This leads to increased neuronal activity and seizure-like behavior. Our results identify the chromatin remodeler Brg1 as an important regulator of inhibitory neurotransmission and seizure susceptibility, which may be important for understanding epilepsy associated with neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Rac1 contributes to brain connectivity impairments and neuropsychiatric disorders in Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by inactivating mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mTOR complex 1 pathway. Patients commonly present with epilepsy and TSC-associated neuropsychiatric disorders (TANDs), including intellectual disability and anxiety. Our previous work identified anxiety-like behavior in tsc2vu242 zebrafish mutants, characterized by enhanced thigmotaxis. We found that anxiety-like behavior in tsc2vu242 zebrafish mutants was rescued by Rac1 inhibitors. These findings prompted further investigation into Rac1 signaling in the context of TSC pathology. Using G-LISA and FRET live imaging, we confirmed elevated Rac1 activity in the mutant brains. Rac1 activity was reduced following NSC23766 and EHT1864 treatment. Compared to wild-type controls, Rac1 activity in mutants was elevated by 50% in untreated animals, and reduced by [~]30-40% after Rac1 inhibitors. Moreover, aberrant connectivity between brain hemispheres that correlated with anxiety before was restored after Rac1 inhibition. Transcriptomic profiling revealed 1,260 DEGs between homozygous and heterozygous tsc2vu242 zebrafish. Rac1 inhibition restored the expression of approximately 1,000 genes toward wild-type levels. KEGG pathway analysis identified significant enrichment in mTOR signaling and focal adhesion, while GO terms highlighted processes including axon guidance, axonogenesis, and neuronal projection. Collectively, our findings support a functional role for Rac1 in TSC pathology, linking cytoskeletal dysregulation with aberrant axon development and anxiety-like behavior. Rac1 inhibition emerges as a promising therapeutic avenue for modulating both brain structure and function in TSC-associated anxiety. HighlightsO_LIRac1 activity is upregulated in tsc2vu24/vu242 zebrafish mutants and correlates with anxiety-like behavior. C_LIO_LIInhibition with NSC23766 and EHT1864 reduces Rac1 activity, partially normalizes mTORC1 signaling, and rescues anxiety-like behavior. C_LIO_LILive FRET imaging and G-LISA confirm elevated Rac1 signaling and its modulation by pharmacological treatment. C_LIO_LITranscriptomic profiling reveals 1,260 deferentially expressed genes in mutants, with restoration of [~]1,000 genes by NSC23766. C_LIO_LIGene expression and pathway analysis link Rac1 dysregulation to altered actin dynamics, axon guidance, and focal adhesion. C_LI

neuroscience↗

bioRxiv2025

Evolutionary Perspectives on Anxiety: Telencephalic Circuitry and the Anxiogenic Role of TrkB Signaling in Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC) is a genetic disease which manifests as a range of neurological symptoms, including benign brain tumors, epilepsy, and TSC-associated neuropsychiatric disorders (TANDs). Among the latter, according to recent reports, anxiety and mood disorders affect over 50% of patients. We have previously demonstrated anxiety-like behavioral symptoms in the zebrafish model of TSC, which were rescued by treatment with the TrkB antagonist ANA-12. Here, we aimed to investigate the mechanism of how ANA-12 regulates behavior by analyzing brain activity in the telencephalon of TSC zebrafish larvae, and we identified the affected regions as corresponding to the known mammalian circuitry involved in anxiety processing. Due to differences in development, the identification of telencephalic territories that are homologous between zebrafish and mammals remains challenging, particularly at early, dynamic stages of development. However, we were able to identify populations of neurons in the zebrafish habenula and ventral subpallium whose involvement in anxiety parallels that of mammals. Those regions were dysregulated in the TSC mutant. This dysregulation correlated with aberrant anxiety behavior and was rescued by treatment with ANA-12. Our results suggest that hyperactivation of TrkB in those regions is a major contributor to anxiety-like behavior as seen in TSC fish, and that those mechanisms could be evolutionarily conserved between zebrafish and mammals.

neuroscience↗

bioRxiv2022

mTORC1 hyperactivation causes sensory integration deficits due to habenula impairment

Mechanistic target of rapamycin complex 1 (mTORC1) is an integration hub for extracellular and intracellular signals necessary for proper brain development. Hyperactivation of mTORC1 is found in many developmental diseases, including autism spectrum disorder (ASD). Atypical reactivity to sensory stimuli is often found in patients with ASD. The most frequent hereditary cause of ASD is Tuberous Sclerosis Complex (TSC), in which inactivating mutations in the TSC1 or TSC2 genes result in hyperactivation of the mTORC1 pathway. We have discovered that the zebrafish model of TSC, tsc2vu242/vu242 mutants lack light preference, a behavior requiring integration of multiple sensory inputs. Here, we show that the lack of light preference in tsc2vu242/vu242 zebrafish is caused by aberrant sensory integration of light stimuli in the left dorsal habenula. Single-cell calcium imaging analysis revealed that tsc2vu242/vu242 fish showed impaired function of the left dorsal habenula, in which neurons exhibited higher activity and lacked habituation to the light stimuli resulting in atypical response to light. Lack of light-preference behavior and abnormal neuronal activity in the left dorsal habenula were rescued by rapamycin, indicating that hyperactive mTorC1 causes aberrant habenula function and impaired sensory integration resulting in lack of light preference. Our results link sensory integration deficits seen in TSC patients suffering from ASD with hyperactive mTORC1 and suggest that mTORC1 hyperactivity contributes to atypical reactivity to sensory stimuli in ASD.

neuroscience↗