Biology subjects

Kurrasch, D.

Publications and source records attributed to Kurrasch, D..

7 recordsLinked to original sources

bioRxiv2025

Inhibition of phosphodiesterase 4B as a novel therapeutic strategy for the treatment of refractory epilepsy

Despite the availability of nearly 40 approved anti-seizure medications (ASMs), at least one-third of individuals with epilepsy remain refractory to treatment, and many experience life-limiting cognitive or psychiatric side effects. Using a machine learning-guided platform, we identified PDE4 as an underexplored anti-seizure target, which became further validated based on its enriched expression in seizure-relevant brain regions and its potential to modulate excitatory/inhibitory neuronal tone via cAMP signaling. The pan-PDE4 inhibitor crisaborole partially protected against hyperthermia-induced seizures and reduced spontaneous seizures in Scn1a+/- mice, while rolipram and roflumilast showed no efficacy at tolerable doses. SN-2000, a first-in-kind allosteric modulator of PDE4B, was rationally designed for isoform selectivity and brain penetration, and demonstrated versatile reduction of seizure activity across multiple zebrafish and rodent genetic and acquired epilepsy models, with efficacy comparable to standard-of-care ASMs. SN-2000 also demonstrated favorable behavioral outcomes, reducing post-ictal aggression and anxiety-like behaviors, and improving cognitive performance in both wild-type and epileptic mice. These effects were linked to paradoxical regulation of excitatory and neuronal activity in the cortex and thalamus of epileptic mice, respectively, as well as elevated cAMP signaling and downstream pCREB activation. Together, these findings support PDE4B inhibition as a disease-relevant mechanism in epilepsy, and position SN-2000 as a promising therapeutic candidate offering seizure control without the neuropsychiatric burden of existing ASMs and potential pro-cognitive properties. One Sentence SummarySN-2000, a novel allosteric PDE4 inhibitor, reduces seizure activity and shows psychiatric-neutral and pro-cognitive properties in preclinical models

neuroscience↗

bioRxiv2024

Glycolytic flux controls retinal progenitor cell differentiation via regulating Wnt signaling

Metabolic pathways are remodeled in response to energy and other homeostatic demands and are dynamically regulated during embryonic development, suggesting a role in guiding cellular differentiation. Here, we show that glycolytic flux is required and sufficient to bias multipotent retinal progenitor cells (RPCs) to acquire a rod photoreceptor fate in the murine retina. In RPC-specific Phosphatase and tensin homolog conditional knock-out (Pten-cKO) and RPC-specific conditional gain-of-function of dominant active PFKB3 (cytoPFKB3) mice, glycolytic gene expression and activity are elevated, correlating with precocious rod photoreceptor differentiation and outer segment maturation. Conversely, glycolytic inhibition in retinal explants suppresses RPC proliferation and photoreceptor differentiation, achieved either with 2-deoxy-d-glucose, a competitive inhibitor of glucose metabolism, by lowering media pH, which disables PKM2, a rate-limiting enzyme, or by inhibiting lactate/H+ symporters, which lowers intracellular pH. Mechanistically, we show that Wnt signaling, the top-upregulated pathway in Pten-cKO retinas, is a glycolysis-dependent pathway. Pharmacological and genetic perturbation of Wnt signaling by knocking-out Ctnnb1, encoding {beta}-catenin, phenocopies glycolytic inhibition, suppressing RPC proliferation, photoreceptor differentiation and outer segment maturation. Thus, developmental rewiring of glycolytic flux modulates Wnt signaling to drive rod photoreceptor differentiation and maturation, an instructive role that may be exploited therapeutically for cell replacement strategies. IMPACT STATEMENTTransgenic and pharmacological approaches reveal developmental elevations in glycolytic flux have an instructive role in promoting rod photoreceptor differentiation and maturation via activation of Wnt signaling.

developmental biology↗

bioRxiv2022

Hypothalamic vasopressin sex differentiation is established during embryonic neurogenesis

Arginine vasopressin (AVP) is a conserved sexually dimorphic system regulating behaviors and physiologies. Decades of research concludes that AVP sex differentiation in mice occurs around birth when a gonadal surge of testosterone is converted to estrogen in male sexual dimorphic brain regions. We discovered that AVP neurons in the murine hypothalamus are sexually dimorphic much earlier than this surge, with male mice displaying more AVP neurons than females during neurogenesis at E11. In utero exposure to a pan-ER antagonist blocked AVP masculinization in males, whereas embryonic exogenous 17{beta}-estradiol or xenoestrogen bisphenol A (BPA) masculinized female AVP neurons, causing permanent masculinization effects on adult female AVP cell numbers, projections and intrinsic neuronal properties. Our data reveal that sexual dimorphism of hypothalamic AVP neurons is present from the earliest stages of their differentiation and challenges current dogma that masculinization of the male brain occurs around birth. One-Sentence SummarySexual dimorphism of hypothalamic vasopressin is established during neurogenesis and exposure to the xenoestrogen bisphenol A during pregnancy induces masculinization of female brains

neuroscience↗

bioRxiv2022

EXPOSURE TO GLYPHOSATE OR ROUNDUP DURING ZEBRAFISH EMBRYOGENESIS DIFFERENTIALLY AFFECTS METABOLISM AND SWIMMING BEHAVIOURS

Glyphosate-based herbicides (GBHs), the most recognized of which is Roundup, are the most extensively used herbicides worldwide. GBHs were initially considered safe for animals since the primary target of the active ingredient, glyphosate, is only found in plants. Recent studies show that glyphosate can affect a range of animal physiologies; however, it remains poorly characterized as to whether animal GBH effects are mediated by glyphosate itself or are in response to toxic effects of the adjuvants and surfactants found in GBH formulations. Here we expose embryonic zebrafish to environmentally relevant doses of glyphosate or Roundup and compare effects on two systems in the larvae: cellular bioenergetics, since glyphosate can affect mitochondrial function, and behaviour, as a systems-level readout of lasting developmental changes. We showed that exposure of embryonic zebrafish to low levels of glyphosate resulted in decreased mitochondrially-mediated basal respiration and hypoactive swimming behavior in larval stage, whereas exposure to Roundup in this same treatment paradigm had the opposite effect, causing increased cellular respiration and increased locomotion. In addition, we also explored generational effects of F1 embryonic glyphosate or Roundup exposure in the F2, and showed that offspring born to zebrafish exposed to low-level glyphosate or Roundup during embryogenesis both exhibited reduced mitochondrially-mediated basal respiration and altered locomotion. Combined, these data show that embryonic exposure to glyphosate or the full formulation of GBHs caused differential effects on mitochondrial function and behaviours in vertebrates, with potential lasting effects on future generations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/510731v1_fig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@93431borg.highwire.dtl.DTLVardef@1aa602org.highwire.dtl.DTLVardef@1890cf5org.highwire.dtl.DTLVardef@b1c655_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1.C_FLOATNO Graphical abstract.Zebrafish (F1 generation) were exposed to glyphosate or Roundup from zero to 48 hours, with behaviour and mitochondrial bioenergetics assessed at larval timepoints (2- and 5-dpf). Offspring of glyphosate and Roundup exposed fish (F2 generation) behaviour and mitochondrial bioenergetics were assessed to the same paradigm as F1 fish at 5-dpf. Changes to core metabolic parameters and locomotion was observed in both F1 and F2 generations. C_FIG

neuroscience↗

bioRxiv2022

The Ketogenic Diet Metabolite β-Hydroxybutyrate Promotes Mitochondrial Elongation via Deacetylation and Improves Autism-like Behavior in Zebrafish

The ketogenic diet (KD) is clinically beneficial and has therapeutic potential across a growing list of neurological disorders, including autism spectrum disorder (ASD). However, the underlying mechanisms mediating the benefits of the KD, which can also have undesirable side effects, remain undefined. To this end, improvements in mitochondrial morphology and function correlate with improved ASD behaviours in response to the KD, though how the KD influences mitochondrial morphology, and whether this is sufficient to improve behaviour remains unknown. Here, we investigate how beta-hydroxybutyrate (BHB), a key metabolite produced by the KD regulates mitochondrial morphology in HeLa cells, and whether this pathway could be exploited to alter phenotypes in a zebrafish model of ASD. We found that {beta}-oxidation of BHB promotes mitochondrial elongation in HeLa cells by increasing NAD+ levels, which in turn activates SIRT deacetylases that act on key regulators of both mitochondrial fusion and fission. Our data suggest that increasing NAD+ levels with its precursor, nicotinamide mononucleotide (NMN), is sufficient to promote mitochondrial hyperfusion. Finally, both BHB and NMN impact neurodevelopment in the shank3b+/- zebrafish model of ASD. Together, our findings elucidate a mechanism by which the ketogenic diet promotes mitochondrial elongation. Moreover, manipulation of this pathway may provide a novel avenue for the treatment of neurological disorders such as ASD that also may obviate potential complications of the KD in clinical practice.

molecular biology↗

bioRxiv2022

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

Epilepsy is at times a fatal disease. Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in people with intractable epilepsy and is defined by exclusion; non-accidental, non-toxicologic, and non-anatomic causes of death. While SUDEP often follows a bilateral tonic-clonic seizure, the mechanisms that ultimately lead to terminal apnea and then asystole remain elusive and there is a lack preventative treatments. Based on the observation that discrete seizures lead to local vasoconstriction, resulting in hypoperfusion, hypoxia and behavioural disturbances in the forebrain (Farrell et al., 2016), we reasoned that similar mechanisms may play a role in SUDEP when seizures invade the brainstem. Here we tested this neurovascular-based hypothesis of SUDEP in awake non-anesthetized mice by pharmacologically preventing seizure-induced vasoconstriction, with cyclooxygenase-2 or L-type calcium channel antagonists. In both acute and chronic mouse models of SUDEP, ibuprofen and nicardipine extended life. We also examined the potential role of spreading depolarization in the acute model of SUDEP. These data provide a proof of principle for the neurovascular hypothesis of SUDEP and the use of currently available treatments to prevent it.

neuroscience↗

bioRxiv2020

Proneural genes define ground state rules to regulate neurogenic patterning and cortical folding

Transition from smooth, lissencephalic brains to highly-folded, gyrencephalic structures is associated with neuronal expansion and breaks in neurogenic symmetry. Here we show that Neurog2 and Ascl1 proneural genes regulate cortical progenitor cell differentiation through cross-repressive interactions to sustain neurogenic continuity in a lissencephalic rodent brain. Using in vivo lineage tracing, we found that Neurog2 and Ascl1 expression defines a lineage continuum of four progenitor pools, with double+ progenitors displaying several unique features (least lineage-restricted, complex gene regulatory network, G2 pausing). Strikingly, selective killing of double+ progenitors using split-Cre;Rosa-DTA transgenics breaks neurogenic symmetry by locally disrupting Notch signaling, leading to cortical folding. Finally, consistent with NEUROG2 and ASCL1 driving discontinuous neurogenesis and folding in gyrencephalic species, their transcripts are modular in folded macaque cortices and pseudo-folded human cerebral organoids. Neurog2/Ascl1 double+ progenitors are thus Notch-ligand expressing niche cells that control neurogenic periodicity to determine cortical gyrification. HIGHLIGHTSO_LINeurog2 and Ascl1 expression defines four distinct transitional progenitor states C_LIO_LIDouble+ NPCs are transcriptionally complex and mark a lineage branch point C_LIO_LIDouble+ NPCs control neurogenic patterning and cortical folding via Notch signaling C_LIO_LINeurog2 and Ascl1 expression is modular in folded and not lissencephalic cortices C_LI eTOC BLURBEmergence of a gyrencephalic cortex is associated with a break in neurogenic continuity across the cortical germinal zone. Han et al. identify a pool of unbiased neural progenitors at a lineage bifurcation point that co-express Neurog2 and Ascl1 and produce Notch ligands to control neurogenic periodicity and cortical folding.

developmental biology↗