Biology subjects

Borgkvist, A.

Publications and source records attributed to Borgkvist, A..

3 recordsLinked to original sources

bioRxiv2024

5-HT1B receptors mediate dopaminergic inhibition of vesicular fusion and GABA release from striatonigral synapses.

The substantia nigra pars reticulata (SNr), a crucial basal ganglia output nucleus, contains a dense expression of dopamine D1 receptors (D1Rs), along with dendrites belonging to dopaminergic neurons of substantia nigra pars compacta. These D1Rs are primarily located on the terminals of striatonigral medium spiny neurons, suggesting their involvement in the regulation of neurotransmitter release from the direct pathway in response to somatodendritic dopamine release. To explore the hypothesis that D1Rs modulate GABA release from striatonigral synapses, we conducted optical recordings of striatonigral activity and postsynaptic patch-clamp recordings from SNr neurons in the presence of dopamine and D1R agonists. We found that dopamine inhibits optogenetically triggered striatonigral GABA release by modulating vesicle fusion and Ca2+ influx in striatonigral boutons. Notably, the effect of DA was independent of D1R activity but required activation of 5-HT1B receptors. Our results suggest a serotonergic mechanism involved in the therapeutic actions of dopaminergic medications for Parkinsons disease and psychostimulant-related disorders.

neuroscience↗

bioRxiv2024

Dysregulated acetylcholine-mediated dopamine neurotransmission in the eIF4E Tg mouse model of autism spectrum disorders.

Autism Spectrum Disorders (ASD) consist of diverse neurodevelopmental conditions where core behavioral symptoms are critical for diagnosis. Altered dopamine neurotransmission in the striatum has been suggested to contribute to the behavioral features of ASD. Here, we examine dopamine neurotransmission in a mouse model of ASD characterized by elevated expression of the eukaryotic initiation factor 4E (eIF4E), a key regulator of cap-dependent translation, using a comprehensive approach that encompasses genetics, behavior, synaptic physiology, and imaging. The results indicate that increased eIF4E expression leads to behavioral inflexibility and impaired striatal dopamine release. The loss of normal dopamine neurotransmission is due to a defective nicotinic receptor signaling that regulates calcium dynamics in dopaminergic axons. These findings reveal an intricate interplay between eIF4E, DA neurotransmission, and behavioral flexibility, provide a mechanistic understanding of ASD symptoms and offer a foundation for targeted therapeutic interventions.

neuroscience↗

bioRxiv2022

Deficiency of Heterogeneous Nuclear Ribonucleoprotein U leads to delayed neurogenesis

Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level. HNRNPU downregulation leads to altered neurogenesis and an increased fraction of neural progenitors in the maturing neuronal population. We conclude that, HNRNPU locus is involved in delayed commitment of neural progenitors to neuronal maturation in cell types with hindbrain profile.

neuroscience↗