Biology subjects

Martinez-Gallego, I.

Publications and source records attributed to Martinez-Gallego, I..

6 recordsLinked to original sources

bioRxiv2026

Mitochondrial pyruvate import in astrocytes links anaplerosis to seizure resistance

Astrocytes are glycolytic cells that convert a substantial fraction of glucose-derived pyruvate into lactate, a metabolite implicated in supporting neuronal energy demand and modulating excitability, plasticity and memory. This view has placed astrocytic lactate production and export at the centre of astrocyte-neuron metabolic coupling, but whether mitochondrial pyruvate utilization in astrocytes is dispensable in vivo or fulfils an essential function in the intact brain remains unknown. Here we show that adult astrocyte-specific deletion of Mpc2, encoding an obligatory mitochondrial pyruvate carrier subunit, causes motor deficits, neuronal hyperexcitability and seizure-associated lethality. Metabolic profiling revealed pyruvate diversion toward alanine as an unsuccessful compensatory bypass, together with impaired tricarboxylic acid-cycle metabolism and an imbalance in neurotransmitter-related pools, including glutamate, glutamine and {gamma}-aminobutyric acid. Thus, astrocytic mitochondrial pyruvate import is not primarily required for bioenergetic purposes but acts as a non-redundant anaplerotic gate that maintains neurotransmitter homeostasis, excitation-inhibition balance and seizure resistance in vivo.

neuroscience↗

bioRxiv2025

A serotonergic mechanism is involved in the pro-cognitive effect of AM6545 treatment in a mouse model of fragile X syndrome

Fragile X syndrome (FXS) is the principal monogenic syndrome leading to inherited intellectual disability and autism. It is caused by the silencing of FMR1 gene that leads to the loss in the expression of its encoded protein, the fragile X messenger ribonucleoprotein 1 (FMRP). In synapses, FMRP has a key role in local mRNA modulation to maintain synaptic plasticity. The Fmr1 KO (FX) mouse model shows cognitive impairment and some of the synaptic traits present in individuals with FXS together with alterations in gut microbiota. Previous studies revealed that pharmacological and genetic cannabinoid type-1 receptor (CB1R) inhibition significantly prevented central key alterations in FX mice. Here, we aimed to evaluate the effect of a sub-chronic treatment with the largely peripherally-restricted CB1R antagonist AM6545. We found that AM6545 reduced memory deficits and restored enhanced hippocampal mGluR5-dependent long-term depression and aberrant dendritic spine density in FX mice. At the peripheral level, AM6545 modified altered FX mice fecal microbiota composition, while in the hippocampus AM6545 treatment upregulated hippocampal Htr4, the gene encoding for serotonin receptor 4 (5-HT4R) This upregulation positively correlated with memory performance. Notably, acute pharmacological blockade of 5-HT4R abolished the pro-cognitive effect produced by AM6545. Together, our results suggest that peripheral CB1R inhibition ameliorates key alterations in FX mouse model and modifies the expression of serotonergic receptors important for cognitive performance.

animal behavior and cognition↗

bioRxiv2024

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic, and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheime[r]s disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

neuroscience↗

bioRxiv2023

Sub-chronic peripheral CB1R inhibition enhances cognitive performance and induces hippocampal synaptic plasticity changes in naive mice

Background and PurposeThe peripheral contribution to brain function and cognitive performance is far from understood. Cannabinoid type-1 receptor (CB1R) is classically pictured in the central nervous system to have such a role. We previously demonstrated a novel mechanism where the acute peripheral CB1R inhibition in mice prolongs memory persistence. Here, we take advance of the repeated exposure to the peripherally-restricted CB1R antagonist to further reveal cognitive improvements and the hippocampal mechanisms involved. Experimental ApproachWe evaluated in young adult male and female mice the behavioural consequences of a sub-chronic treatment with AM6545. Moreover, an unbiased transcriptomic analysis, as well as electrophysiological and biochemical studies, were performed in the hippocampus of treated mice to elucidate the central cellular and molecular consequences of such peripheral approach. Key ResultsSub-chronic inhibition of peripheral CB1R with AM6545 resulted in enhanced memory in low and high arousal conditions. Moreover, executive function was facilitated after repeated AM6545 administration, further strengthening the cognitive improving properties of peripheral CB1R inhibition. Transcriptional analysis of hippocampal synaptoneurosomes from treated male and female mice revealed a sex-dependent modulation of synaptic transcripts by AM6545. Notably, AM6545 occluded long-term potentiation in CA3-CA1 synapses while enhancing input-output relation. This was accompanied by an increase in the hippocampal expression of Bdnf and Ngf. Conclusion and ImplicationsOur results show that peripheral CB1R inhibition contributes to the modulation of memory persistence, executive function, and hippocampal synaptic plasticity in mice, further indicating that peripheral CB1R could act as a target for a novel class of nootropic compounds. What is already known?- Acute peripheral CB1R inhibition enhances object-recognition memory persistence in mice. - Such enhancement occurs through a noradrenergic mechanism involving the vagus nerve. What does this study add?- Peripheral CB1R inhibition modifies synaptoneurosomal transcriptome in the hippocampus of mice. - No tolerance and no side effects were observed after peripheral CB1R inhibition. What is the clinical significance?- Peripheral CB1R inhibition may function as a novel strategy for cognitive improvement.

neuroscience↗

bioRxiv2023

Differential neural circuit vulnerability to β-amyloid and tau pathologies in novel Alzheimer disease mice

Alzheimers disease (AD) progresses with memory loss and neuropsychiatric symptoms associated with cell specific vulnerability in memory- and emotion-related neural circuits. Neuropathological and synaptic changes are key factors influencing the clinical progression to dementia, but how they cooperate to cause memory and emotional disturbances is largely unknown. Here, we employed pathological, behavioral, expansion microscopy, electrophysiology and transcriptomic approaches to evaluate the effects of amyloid-{beta} (A{beta}) and tau on neuropathological progression, synaptic function, and memory and emotional symptoms in amyloid precursor protein (APP), Tau and double novel APP/Tau transgenic mice expressing the mutant human amyloid precursor protein (APPSw,Ind) and/or microtubule-associated protein tau (MAPT) in excitatory neurons. APP/Tau mice of both sexes show spatial learning and memory deficits associated with synaptic tau accumulation and reduced synaptic proteins and neurotransmission in the hippocampus. By contrast, male and female APP/Tau mice exhibit innate anxious behavior and impaired fear memory extinction linked to A{beta} pathology and with absence of synaptic tau in the basolateral amygdala (BLA). Intriguingly, APP/Tau mice show NMDA-dependent long-term potentiation (LTP) deficits in the hippocampus but not in the amygdala. Bulk RNA sequencing reveals region-specific but also common transcriptional changes in response to A{beta}/tau pathology, including downregulation of synapse transmission and ion channel activity genes. Importantly, we detected 65 orthologs of human AD risk genes identified in GWAS (e.g., APOE, BIN1, CD33, CLU, PICALM, PLCG2, PTK2B, TREM2, SORL1, USP6NL) differentially expressed in the hippocampus and/or BLA of APP/Tau mice, indicating that this APP/Tau model exhibits transcriptional alterations linked to known molecular determinants of AD development. In conclusion, simultaneous development of A{beta} and tau neuropathologies in this double APP/Tau transgenic mouse model reproduces synaptic, behavioral, and molecular alterations associated with AD pathophysiology in a region-specific manner. Our findings highlight region-specific pathological effects of A{beta} and tau in excitatory neuronal circuits mediating emotional and memory processing, providing evidence that both factors and their molecular cascades should be considered in future AD preventive and therapeutic strategies. Graphical abstractAge-dependent vulnerability of memory and emotional neural circuits in response to tau and A{beta} pathologies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/536603v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@efbe90org.highwire.dtl.DTLVardef@1c7f1dborg.highwire.dtl.DTLVardef@1d7764borg.highwire.dtl.DTLVardef@9738ec_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Arg1+ microglia are critical for shaping cognition in female mice

Diversity within microglia, the resident brain immune cells, is reported. Whether microglial subsets constitute different subtypes with intrinsic properties and unique functions has not been fully elucidated. Here, we describe a microglial subtype characterized by the expression of the enzyme Arginase-1, i.e. Arg1 +microglia, which is found predominantly in the cholinergic neuron-rich forebrain region during early postnatal development. Arg1+ microglia are frequently observed in close apposition to neurons and exhibit a distinctive molecular signature reflecting a reactive profile. Arg1 deficiency in microglia results in impaired dendritic spine maturation in the hippocampus where cholinergic neurons project, and cognitive behavioural deficiencies in female mice. Our results expand on microglia diversity and provide insights into distinctive spatiotemporal functions exerted by microglial subtypes.

neuroscience↗