Browsing by Author "Gajardo, Ivana"

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    A centronuclear myopathy-causing mutation in dynamin-2 disrupts neuronal morphology and excitatory synaptic transmission in a murine model of the disease
    (2023) Arriagada-Diaz, Jorge; Flores-Munoz, Carolina; Gomez-Soto, Barbara; Labrana-Allende, Marjorie; Mattar-Araos, Michelle; Prado-Vega, Lorena; Hinostroza, Fernando; Gajardo, Ivana; Guerra-Fernandez, Maria Jose; Bevilacqua, Jorge A.; Cardenas, Ana M.; Bitoun, Marc; Ardiles, Alvaro O.; Gonzalez-Jamett, Arlek M.
    AimsDynamin-2 is a large GTPase, a member of the dynamin superfamily that regulates membrane remodelling and cytoskeleton dynamics. Mutations in the dynamin-2 gene (DNM2) cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterised by progressive weakness and atrophy of the skeletal muscles. Cognitive defects have been reported in some DNM2-linked CNM patients suggesting that these mutations can also affect the central nervous system (CNS). Here we studied how a dynamin-2 CNM-causing mutation influences the CNS function. MethodsHeterozygous mice harbouring the p.R465W mutation in the dynamin-2 gene (HTZ), the most common causing autosomal dominant CNM, were used as disease model. We evaluated dendritic arborisation and spine density in hippocampal cultured neurons, analysed excitatory synaptic transmission by electrophysiological field recordings in hippocampal slices, and evaluated cognitive function by performing behavioural tests. ResultsHTZ hippocampal neurons exhibited reduced dendritic arborisation and lower spine density than WT neurons, which was reversed by transfecting an interference RNA against the dynamin-2 mutant allele. Additionally, HTZ mice showed defective hippocampal excitatory synaptic transmission and reduced recognition memory compared to the WT condition. ConclusionOur findings suggest that the dynamin-2 p.R465W mutation perturbs the synaptic and cognitive function in a CNM mouse model and support the idea that this GTPase plays a key role in regulating neuronal morphology and excitatory synaptic transmission in the hippocampus.
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    Whole-brain neuronal MCT2 lactate transporter expression links metabolism to human brain structure and function
    (National Academy of Sciences, 2022) Medel Sierralta, Vicente Nicolas; Crossley Karmelic, Nicolas Andrés; Gajardo, Ivana; Muller, Eli; Barros L., Felipe; Shine, James N.; Sierralta, Jimena
    Brain activity is constrained by local availability of chemical energy, which is generatedthrough compartmentalized metabolic processes. By analyzing data of whole humanbrain gene expression, we characterize the spatial distribution of seven glucose andmonocarboxylate membrane transporters that mediate astrocyte–neuron lactate shuttletransfer of energy. We found that the gene coding for neuronal MCT2 is the onlygene enriched in cerebral cortex where its abundance is inversely correlated withcortical thickness. Coexpression network analysis revealed that MCT2 was the onlygene participating in an organized gene cluster enriched in K+dynamics. Indeed, theexpression of KATPsubunits, which mediate lactate increases with spiking activity, isspatially coupled to MCT2 distribution. Notably, MCT2 expression correlated withfluorodeoxyglucose positron emission tomography task-dependent glucose utilization.Finally, the MCT2 messenger RNA gradient closely overlaps with functional MRI brainregions associated with attention, arousal, and stress. Our results highlight neuronalMCT2 lactate transporter as a key component of the cross-talk between astrocytes andneurons and a link between metabolism, cortical structure, and state-dependent brain function.