Biology subjects

Esteban, J. A.

Publications and source records attributed to Esteban, J. A..

6 recordsLinked to original sources

bioRxiv2026

Neurogranin enhances spontaneous activity and neuronal survival of hippocampal neurons

Neurogranin (Ng) is a postsynaptic protein highly enriched in forebrain neurons and implicated in synaptic plasticity through its ability to bind calmodulin. However, its impact on neuronal development, network dynamics, and cellular homeostasis remains incompletely understood. In this study, we examined the effects of manipulating Ng expression in primary hippocampal neurons using viral gene delivery, with emphasis on structural, functional, and molecular outcomes. Restoring Ng expression to adult physiological levels enhanced dendritic growth, increased synaptic number, and induced a proximal shift of the axon initial segment, consistent with adaptive responses to increased connectivity. Functionally, Ng markedly increased spontaneous neuronal activity and network synchronization, even under culture conditions that normally show minimal baseline activity. Electrophysiological recordings revealed enhanced burst firing and spike synchrony, indicating strengthened functional coupling rather than increased membrane excitability. Ng-dependent activity required action potential firing and glutamatergic transmission. At the molecular level, Ng increased total calmodulin levels in a binding-dependent manner, reduced overall calcium/calmodulin-dependent protein kinase II abundance while enhancing its relative autophosphorylation, and selectively decreased both total and surface levels of ionotropic glutamate receptors. These changes are consistent with a coordinated homeostatic reorganization of calcium-dependent signaling. Despite robust increases in activity, Ng expression improved neuronal viability, reduced cellular stress markers, and increased expression of the anti-apoptotic protein Bcl-2. Active caspase-3 was selectively elevated without triggering apoptosis, suggesting a non-apoptotic role in activity-dependent structural remodeling. Together, these findings identify Ng as a homeostatic regulator that promotes coordinated network activity, adaptive synaptic remodeling, and neuronal survival.

neuroscience↗

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↗

bioRxiv2022

The cell cycle regulator cyclin D1 modulates the activity of α4-containing GABAA receptors

Cyclin D1 (Ccnd1){middle dot}Cdk4 complexes drive cell cycle progression through phosphorylation of pRb. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, the cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the 4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1{middle dot}Cdk4. Ccnd1 binds to an intracellular loop in 4 and, together with Cdk4, phosphorylates the 4 subunit at threonine 423 and serine 431. These modifications increase the activity of 4-containing GABAARs, measured in whole-cell patch-clamp recordings, and upregulate its surface levels. In agreement with this role of Ccnd1{middle dot}Cdk4 in neuronal signaling, inhibition of Cdk4 decreases synaptic and extrasynaptic currents in the hippocampus of newborn rats. Moreover, CCND1 knockout mice display an altered pattern of dendritic spines, according to 4 functions in synaptic pruning. Overall, our findings molecularly link Ccnd1{middle dot}Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signaling.

molecular biology↗

bioRxiv2020

Constitutive ghrelin receptor activity modulates AMPA receptor traffic and supports memory formation

The ability of animals to store and retrieve food caches in the wild requires the integration of biological signals of hunger, satiety and memory. The role of ghrelin in regulating feeding and memory makes ghrelin receptors an important target to shape the required cellular and molecular responses. We investigated the effects of the high ligand-independent activity of the ghrelin receptor on the physiology of excitatory synapses. Blocking this type of activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845. Impaired constitutive activity from the ghrelin receptor increased surface diffusion of AMPA receptors and impaired AMPA receptor synaptic delivery mediated by chemical long-term potentiation. These observations support a role for the constitutive activity of the ghrelin receptor in regulating AMPA receptor trafficking under basal conditions and synaptic plasticity. Accordingly, we found that blocking the ghrelin receptor constitutive activity impairs spatial and recognition memory. Impact statementThis work uncovers a role for the constitutive activity of the ghrelin receptor in memory, and in the regulation of the synaptic levels of AMPA receptors, their mobility and synaptic plasticity. Underscoring the importance of deciphering the physiological role of constitutive ghrelin receptor activity, ghrelin receptor inverse agonism is now being considered as a therapy to treat alcohol use disorder.

neuroscience↗