Biology subjects

Gardier, A. M.

Publications and source records attributed to Gardier, A. M..

3 recordsLinked to original sources

bioRxiv2023

A tale of two receptors: simultaneous targeting of NMDARs and 5-HT4Rs exerts additive effects against stress

BACKGROUNDSerotonin (5-HT) receptors and N-methyl-D-aspartate receptors (NMDARs) have both been implicated in the pathophysiology of depression and anxiety disorders. Here, we evaluated whether targeting both receptors through combined dosing of (R,S)-ketamine, an NMDAR antagonist, and prucalopride, a serotonin type IV receptor (5-HT4R) agonist, would have additive effects, resulting in reductions in stress-induced fear, behavioral despair, and hyponeophagia. METHODSA single injection of saline (Sal), (R,S)-ketamine (K), prucalopride (P), or a combined dose of (R,S)-ketamine and prucalopride (K+P) was administered before or after contextual fear conditioning (CFC) stress in both sexes. Drug efficacy was assayed using the forced swim test (FST), elevated plus maze (EPM), open field (OF), marble burying (MB), and novelty-suppressed feeding (NSF). Patch clamp electrophysiology was used to measure the effects of combined drug on neural activity in hippocampal CA3. c-fos and parvalbumin (PV) expression in the hippocampus (HPC) and medial prefrontal cortex (mPFC) was examined using immunohistochemistry and network analysis. RESULTSWe found that a combination of K+P, given before or after stress, exerted additive effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Combined K+P administration significantly altered c-fos and PV expression and network activity in the HPC and mPFC. CONCLUSIONSOur results indicate that combined K+P has additive benefits for combating stress-induced pathophysiology, both at the behavioral and neural level. Our findings provide preliminary evidence that future clinical studies using this combined treatment strategy may prove advantageous in protecting against a broader range of stress-induced psychiatric disorders.

neuroscience↗

bioRxiv2020

A non-linear relation between levels of adult hippocampal neurogenesis and expression of the immature neuron marker doublecortin

We investigated the mechanisms underlying the effects of the antidepressant fluoxetine on behavior and adult hippocampal neurogenesis (AHN). After confirming our earlier report that the signaling molecule {beta}2-arrestin is required for the antidepressant-like effects of fluoxetine, we found that the effects of fluoxetine on proliferation of neural progenitors and on survival of adult-born granule cells are absent in the {beta}2-arrestin knockout ({beta}2-Arr KO) mice. To our surprise fluoxetine induced a dramatic upregulation of doublecortin (DCX) in the {beta}2-Arr KO mice, indicating that DCX expression can be increased even though AHN is not. We discovered two other conditions where DCX expression is regulated non linearly compared to levels of AHN: a chronic stress model where DCX is upregulated and an inflammation model where DCX is down regulated. We conclude that assessing DCX expression alone to quantify levels of AHN can be misleading and that caution should be applied when label retention techniques are not available. HIGHLIGHTSO_LI{beta}2-arrestin ({beta}-Arr2) is required for the antidepressant-like effects of fluoxetine. C_LIO_LIA dramatic upregulation of doublecortin (DCX) is observed in the {beta}2-Arr KO mice after antidepressant treatment whereas its effects on proliferation of neural progenitors and on survival of adult-born granule cells are absent. C_LIO_LIDCX is more upregulated than the number of young neurons in a mouse model of depression. C_LIO_LIDCX is more down regulated than the number of young neurons in a model of inflammation. C_LIO_LImicroRNAs (miRs) may contribute to the regulation of DCX mRNA expression. C_LI

neuroscience↗

bioRxiv2019

Prophylactic efficacy of 5-HT4R agonists against stress

Enhancing stress resilience could protect against stress-induced psychiatric disorders in at-risk populations. We and others have previously reported that (R,S)-ketamine acts as a resilience enhancing drug (e.g., prophylactic) against stress when administered 1 week before stress. While we have shown that the selective 5-hydroxytryptamine (5-HT) (serotonin) reuptake inhibitor (SSRI) fluoxetine (Flx) is ineffective as a prophylactic, it remains to be determined if other serotonergic drugs could be effective prophylactics. Here, we hypothesized that serotonin 4 receptor (5-HT4R) agonists could be prophylactic against fear, depressive-like, and/or anxiety-like behavior. We tested if three 5-HT4R agonists with varying affinity (e.g., partial or selective agonists) could protect against stress in two mouse strains by utilizing a chronic corticosterone (CORT) administration or a contextual fear conditioning (CFC) paradigm. Mice were administered RS-67,333, prucalopride, or PF-04995274 at varying doses and then 1 week later were subjected to chronic CORT or CFC. Chronic administration of RS-67,333, but not Flx was efficacious as a prophylactic against CORT in C57BL/6NTac mice. A single injection of RS-67,333 attenuated learned fear in male, but not female 129S6/SvEv mice. RS-67,333 was ineffective against stress-induced depressive-like behavior in the forced swim test (FST). A single injection of either prucalopride or PF-04995274 attenuated learned fear and decreased stress-induced depressive-like behavior. These data show that in addition to (R,S)-ketamine, 5-HT4R agonists are also effective prophylactics against stress, suggesting that the 5-HT4R may be a novel target for prophylactic drug development.

neuroscience↗