Biology subjects

Iborra-Lazaro, G.

Publications and source records attributed to Iborra-Lazaro, G..

3 recordsLinked to original sources

bioRxiv2024

Social and Contextual Memory Impairments Induced by Amyloid-β Oligomers are Rescued by Sigma-1 Receptor Activation

Sigma-1 receptors (S1Rs) are widely expressed throughout the central nervous system and modulate neuron intracellular calcium levels, leading to changes in neurotransmitter release and neuronal activity. They also interact with various proteins and signaling pathways, playing a key role in regulating synaptic plasticity in brain areas such as the hippocampus, thereby influencing learning and memory processes. This opens a research avenue to explore S1R modulation as a potential therapeutic target in diseases involving hippocampal synaptic alterations and compromised cognitive processes, such as Alzheimers disease (AD). Here, we hypothesize that pharmacological activation of S1R could counteract synaptic plasticity deficits and hippocampal-dependent cognitive alterations in an early-stage amyloidosis model of Alzheimers disease, induced by intracerebroventricular (icv) administration of A{beta}1-42 oligomers (oA{beta}1-42). For that purpose, we investigate ex vivo CA3-CA1 synaptic plasticity, while in vivo, we performed open field habituation and social recognition tasks to assess contextual and social memory, respectively. Our data show that pharmacological activation of S1Rs with the selective agonist PRE-084 counteract oA{beta}1-42 deleterious effects on CA3-CA1 long-term synaptic plasticity (LTP), and hippocampal-dependent contextual and social memory, without alterations of spontaneous behaviors. Together, these results provide evidence for the role of S1Rs in ameliorating hippocampal synaptic and contextual memory dysfunctions and, for the first time, in early amyloid-induced social memory deficits, highlighting their potential in the development of comprehensive treatments for early AD. Also, the absence of adverse behavioral outcomes associated with PRE-084 treatment accentuates its safety profile, underscoring its potential as a therapeutic agent.

neuroscience↗

bioRxiv2023

Systematic characterization of a non-transgenic Amyloid-beta1-42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

BackgroundOne of the neuropathological hallmarks of Alzheimers disease (AD) is amyloid-{beta} (A{beta}) accumulation in the hippocampus that causes its dysfunction. This disruption includes excitatory/inhibitory imbalance, synaptic plasticity and oscillatory activity impairments, and memory deficits. Although AD prevalence is higher in women than men, the possible sex difference is scarcely explored and information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data of the early amyloidosis stages in females, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of A{beta}1-42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse, in both male and female mice. MethodsTo do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings and spatial (working, short- and long-term) and exploratory habituation memory using Barnes maze or open field habituation tasks respectively. ResultsWe found that A{beta}1-42 administration impairs all forms of memory evaluated, regardless the sex, in a long-lasting manner (up to 17 days post-injection). Furthermore, LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underly memory deficits. ConclusionsIn conclusion, our results provide further evidence of the shifting of LTP/LTD threshold due to a single icv. A{beta}1-42 injection, which underly cognitive deficits in early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.

neuroscience↗

bioRxiv2020

Basal G-protein-gated inwardly rectifying potassium (Kir3/GirK) channels activity governs synaptic plasticity that supports dorsal hippocampus-dependent cognitive functions

G-protein-gated inwardly rectifying potassium (Kir3/GirK) channel is the effector of many G-protein-coupled receptors. Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimers and Parkinsons diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. GirK channels are constitutively activated in the dorsal hippocampus contributing to resting membrane potential, and their synaptic activation compensates any excitation excess. Here, in order to elucidate the role of GirK channels activity in the maintenance of dorsal hippocampus-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined. For that purpose, basal GirK activity was pharmacologically modulated by two specific drugs: ML297, a GirK channel opener, and Tertiapin-Q, a GirK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied pharmacological GirK modulation effect on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular injections of both GirK modulators to study their contribution to CA3-CA1 synapse electrophysiological properties, synaptic plasticity, and learning and memory capabilities during hippocampal dependent tasks. We found that pharmacological disruption of basal GirK activity in dorsal hippocampus, causing either function gain or loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GirK activity must take place in the hippocampus to sustain cognitive functions. Significance StatementThe dorsal hippocampus mostly performs cognitive functions related to contextual/spatial associations. These functions rely on synaptic plasticity processes that are critically ruled by a finely tuned neural excitability. Being the downstream physiological effectors of a variety of G-coupled receptors, activation of G protein-gated inwardly rectifying K+ (GirK) channels induces neurons to hyperpolarize, contributing to neural excitability throughout the control of excitatory excess. Here, we demonstrate that modulation of basal GirK channels activity, causing either function gain or loss, transforms HFS-induced LTP into LTD, inducing deficits in dorsal hippocampus-dependent learning and memory. Together, our data show a crucial GirK activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

neuroscience↗