Biology subjects

Davila, J. C.

Publications and source records attributed to Davila, J. C..

3 recordsLinked to original sources

bioRxiv2023

Bidirectional Modulation Of Synaptic Transmission By Insulin-Like Growth Factor I

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity, and is an essential factor in learning and memory processes. Indeed, we have demonstrated that IGF-IR activation induces long-term potentiation (LTP) of synaptic transmission (LTPIGF-I) both in the barrel cortex, improving object recognition (Noriega-Prieto et al., 2021), and in the prefrontal cortex, facilitating the extinction of conditioned fear (Maglio et al., 2021). However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of NMDAR-dependent LTP at layer 2/3 PNs of the mouse barrel cortex is favored or prevented by IGF-I (10nM) or IGF-I (7nM), respectively, when IGF-I is applied 1 hour before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing LTD of the inhibitory post-synaptic currents (IPSCs), 7nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain. SIGNIFICANCE STATEMENTInsulin-like growth factor-I (IGF-I) signalling plays key regulatory roles in multiple processes of brain physiology, such as learning and memory, and brain pathology, such as Alzheimer disease. Yet, the underlying mechanisms remain largely undefined. Here we demonstrate that IGF-I signalling triggers long-term potentiation (LTP) or long-term depression (LTD) of synaptic transmission at cortical synapses in a concentration dependent manner, thus regulating the induction of Hebbian synaptic plasticity. The present work represents an important conceptual advance in our knowledge of the cellular basis of IGF-I signalling in brain function.

neuroscience↗

bioRxiv2019

The Insulin Receptor In Astrocytes Is Involved In The Entrance Of Circulating Insulin Into The Brain

Circulating insulin enters into the brain through mechanisms that are not yet entirely understood. We now report that mice lacking insulin receptors (IR) in astrocytes show reduced uptake of circulating insulin and blunted brain responses to this circulating hormone, suggesting that astrocytes form part of the cellular pathway in the entrance of circulating insulin into the brain. Since we previously showed that ablation of IR in astrocytes decreases brain glucose uptake, we conclude that astrocytic IRs regulate uptake of circulating glucose and insulin.

neuroscience↗

bioRxiv2018

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Alzheimers disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A{beta}) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimers disease) mice, and found specifically expressed in microglia associated with A{beta} plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar A{beta}. Gal3 deletion decreased the A{beta} burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to A{beta} plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure A{beta}. Importantly, a single intrahippocampal injection of gal3 along with A{beta} monomers in WT mice was sufficient to induce the formation of insoluble A{beta} aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and A{beta} aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD.

neuroscience↗