Biology subjects

Jimenez-Herrera, R.

Publications and source records attributed to Jimenez-Herrera, R..

4 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↗

bioRxiv2024

Low dose of a non-urea selective GIRK channel activator improves hippocampal-dependent synaptic plasticity and memory disrupted by amyloid-β oligomers

Increased neural activity characterizes early Alzheimers disease (AD), serving as a prognostic indicator for disease progression and cognitive decline. Mechanisms that drive this hyperactivity and their behavioral effects remain mostly unrevealed, although normalizing altered excitability levels has been shown to reverse cognitive impairment in early AD, both in animals and humans. Soluble amyloid-{beta} oligomers (oA{beta}) primary accumulate in limbic regions like hippocampus and induce neuronal hyperexcitability and subsequent cognitive deficits by impairing ion channels function. Indeed, G protein-gated inwardly rectifying K+ (GIRK) channels -that control neuronal excitability-are greatly affected and their selective pharmacological activation has already been shown very effective to counteract oA{beta}-induced hyperexcitability and hippocampal dysfunction. However, GIRK gain-of-function in healthy animals disrupts learning, memory and underlying synaptic plasticity, greatly limiting its therapeutic potential in preclinical asymptomatic early AD patients. Therefore, GIRK-based pharmacological treatment needs further investigation to overcome these limitations. Here we tested two doses of a novel, more potent, and neuronal selective GIRK activator, VU0810464, in healthy and early oA{beta}1-42-generated AD male and female mice. Both doses normalized hippocampal synaptic plasticity (long-term potentiation, LTP) and associated spatial object location memory (OLM) without sex dimorphism in AD animals. However, in healthy mice, low VU0810464 dose did not significantly alter LTP and OLM, whereas the high dose disrupted both. Our results suggest that the precise tuning of neural excitability with low dosing of VU0810464 might be a promising strategy to safely treat and prevent hippocampal overexcitation and upstreaming memory deficits in early preclinical asymptomatic phases of AD.

neuroscience↗

bioRxiv2024

Mapping the spatial proteomic signature of dorsal and ventral hippocampus in a mouse model of early Alzheimer's disease: changes in synaptic plasticity-related proteins associated with sexual dimorphism

BackgroundAn initial neuropathological hallmark of Alzheimers disease (AD) is the hippocampal dysfunction caused by amyloid-{beta} (A{beta}) peptides accumulation. Soluble oligomeric forms of A{beta} shift synaptic plasticity induction threshold leading to memory deficits in male and female mice in early amyloidosis models. Some protein changes underlying those deficits have been previously studied, but the spatial distribution within the hippocampus, as well as the potential sex differences, remain unknown. Since each hippocampal region (dorsal vs. ventral) has clearly distinct functionality and connectivity, we postulated that some protein changes may be unique to each and might also be sex-dependent. MethodsAn innovative spatial proteomics study was performed to map whole hippocampal proteome distribution using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry, which allows protein detection with spatial resolution directly on tissue sections. Brains from sixteen adult male and female mice intracerebroventricularly injected with A{beta}1-42 oligomers or vehicle were sectioned. MALDI imaging was performed using a RapifleXTM MALDI TissuetyperTM TOF/TOF mass spectrometer followed by protein identification by traditional tandem mass spectrometry (MS/MS) directly on the tissue. To precisely delineate both dorsal and ventral hippocampus, a Nissl staining was performed on succeeding tissue sections. ResultsOf the 234 detected peptides, significant differences in expression levels were found in 34 proteins, due to treatment, sex, or hippocampal location. Moreover, a significant protein-protein interaction (PPI) was observed, showing a relationship to long-term potentiation (LTP), the functional basis of memory. Accordingly, 14 proteins related to synaptic plasticity and/or AD were selected to further study. Results showed many of the altered protein to modulate glycogen synthase kinase-3{beta} (GSK-3{beta}), a protein widely involved in the regulation of synaptic plasticity induction threshold. In fact, hippocampal GSK-3{beta} was found overactivated suggesting a facilitated long-term depression (LTD) instead of LTP in AD models. ConclusionsThis study offers for the first time the specific protein changes in dorsal/ventral hippocampus in both male and female mice, that modulate GSK-3{beta} activity, providing new insight in the pathogenesis of early AD and valuable potential biomarkers for early diagnosis and therapeutic targets.

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↗