Laura Kristine Rasmussen

Scientific focus areas

• In vitro disease modeling of Parkinson’s disease and neurodevelopmental disorders using human induced pluripotent stem cells (hiPSCs) and CRISPR/Cas9 gene technology

• Experimental stem cell research (dopaminergic and glutamatergic differentiation of iPSCs and neural stem cells)

• Mechanisms of mitochondrial dysfunction, dysregulation of the glutamatergic system, genotype-phenotype correlations of monogenic NDDs.

 

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Current project:

Pathomechanistic insights into GRIA3-related neurodevelopmental disorders using human iPSC-derived glutamatergic neurons with gain- or loss-of-function mutations

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Project description:

Neurodevelopmental disorders (NDDs) are devastating early-onset conditions associated with intractable epilepsy, intellectual disability, developmental delay or regression, motor dysfunction, and autism spectrum disorders. Rare missense mutations in the GRIA1–4 subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - a key mediator of excitatory neurotransmission - have been identified as monogenic causes of NDDs. Notably, GRIA3 missense mutations show an equal distribution of gain-of-function (GoF) and loss-of-function (LoF) effects, which are linked to severe epilepsy and distinct clinical phenotypes. However, the underlying cellular and molecular mechanisms by which these mutations disrupt brain development remain largely unknown. 
This PhD project aims to elucidate the neuropathological consequences of GRIA3 dysfunction by generating isogenic glutamatergic neurons derived from human induced pluripotent stem cells (hiPSCs) carrying clinically relevant GoF and LoF GRIA3 variants. These models will be systematically characterized for alterations in AMPAR signaling, neuronal connectivity, glutamatergic network activity, additional biological functions, and cellular viability using molecular, electrophysiological, and imaging techniques. Furthermore, novel therapeutic strategies will be explored by testing AMPAR-targeting compounds on mutant neurons, aiming to rescue disease-relevant phenotypes. Ultimately, this could offer new hope for improving treatment options in NDDs that currently lack effective therapies