Biology subjects

Lopez-Merino, E.

Publications and source records attributed to Lopez-Merino, E..

3 recordsLinked to original sources

bioRxiv2025

Astrocytic PI3Kα controls synaptic plasticity and cognitive function via serine metabolism

Astrocytes are known to modulate neuronal activity by gliotransmission and through metabolic regulation. However, the connection between these two processes is still poorly defined. In this work we show that the p110 isoform of the phosphatidylinositol 3-kinase (PI3K) in astrocytes is required for long-term potentiation (LTP) and has an impact on learning and memory. Using a specific deletion of p110 from hippocampal astrocytes in adult mice, we found that LTP depends on astrocytic p110 to sustain D-serine levels for the activation of NMDA receptors during LTP induction. This requirement is based on the L-serine biosynthetic pathway of the astrocyte, which is defective in the absence of p110 because of a reduced glycolytic flux. Accordingly, the behavioral impairment in mice lacking p110 can be rescued by in vivo administration of L-serine. These results link for the first time the function of PI3K in astrocytes to cerebral metabolism and its influence in synaptic plasticity and cognition.

neuroscience↗

bioRxiv2024

Deficient Memory, Long-Term Potentiation and Hippocampal Synaptic Plasticity in Galectin-4-KO Mice.

BACKGROUNDBrain function is influenced by the gut through the microbiota-gut-brain axis. Non-physiological microbiota-depletion or induced gut infection in animal models, have been instrumental to link intestinal alterations to cognitive and mood dysfunctions. However, the effects of specific, controlled, physiologically relevant shifts in commensal microbiota composition on brain function remain poorly understood. METHODSMice deficient in galectin-4 (Lgals4-KO) were used in this study. Gut microbiota was analysed by 16S-rRNA sequencing. Cognitive and mood status were evaluated with specific behavioral tests. Long-term potentiation (LTP) was tested ex vivo and in vivo by electrophysiological methods and in vitro by immunofluorescence and western blot. RNA-sequencing was used for transcriptomic analyses. Golgi-Cox staining and transmission electron microscopy were used for quantitative and morphological assessments of dendritic spines and synapses. RESULTSLgals4-KO mice present an altered intestinal commensal microbiota in the absence of pathogens, deficient memory formation, and impaired hippocampal LTP in vivo and ex vivo. Furthermore, Lgals4-KO neurons show a reduced activation of AMPA receptors and of CaMKII upon chemically induced LTP in vitro. These mice also display significantly lower dendritic spine density and shorter spine length in hippocampal dendrites, as well as an increased area of the postsynaptic densities CONCLUSIONSOur results define a new role for galectin-4 in the modulation of commensal bacteria. We also show that the absence of galectin-4 induces changes in gut microbial composition, along with synaptic alterations and memory impairment, supporting our hypothesis that variations in endogenous microbiota may cause or contribute to relevant neurological pathologies.

neuroscience↗

bioRxiv2024

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Decreased dendritic complexity and impaired synaptic function are strongly linked to cognitive decline in Alzheimers disease (AD), and precede the emergence of other neuropathological traits that establish a harmful cycle exacerbating synaptic dysfunction. SFRP1, a glial-derived protein regulating cell-cell communication, is abnormally elevated in the brain of AD patients and related mouse models already at early disease stages. Neutralization of SFRP1 activity in mice reduces the occurrence of protein aggregates, neuroinflammation and prevents the loss of synaptic long-term potentiation (LTP). In this study, we generated transgenic mice that overexpress Sfrp1 in astrocytes to investigate whether LTP loss is due to an early influence of SFRP1 on synaptic function or results from other alterations driving disease progression. We report that SFRP1-overexpressing mice show reduced dendritic complexity and spine density in dentate gyrus granule cells during early adulthood, prior to a significant deficit in LTP response and late onset cognitive impairment. Ultrastructural analysis revealed the loss of small-sized synapses and presynaptic alterations in transgenic mice. Analysis of proteomic changes points to a general decrease in protein synthesis and modifications in the synaptic proteome, particularly of proteins related to synaptic vesicle cycle and synaptic organizers, like neurexin and neuroligin. We propose a model wherein SFRP1 directly impacts on synaptic function, by increasing the availability of synaptic organizing molecules at the synapse. These observations, combined with documented SFRP1 effects on APP processing and microglial activation, imply that SFRP1 contributes to multiple pathological effects in AD, emerging as a promising therapeutic target for this devastating disease.

neuroscience↗