Low-dose S-ketamine exerts antidepressant-like effects via enhanced hippocampal synaptic plasticity in postpartum depression rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Ren Z
PROVIDER: S-EPMC8686162 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Chronic pain often leads to depression, increasing patient suffering and worsening prognosis. While hyperactivity of the anterior cingulate cortex (ACC) appears to be critically involved, the molecular mechanisms underlying comorbid depressive symptoms in chronic pain remain elusive. T cell lymphoma invasion and metastasis 1 (Tiam1) is a Rac1 guanine nucleotide exchange factor (GEF) that promotes dendrite, spine, and synapse development during brain development. Here, we show that Tiam1 orchestrates synaptic structural and functional plasticity in ACC neurons via actin cytoskeleton reorganization and synaptic N-methyl-d-aspartate receptor (NMDAR) stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Notably, administration of low-dose ketamine, an NMDAR antagonist emerging as a promising treatment for chronic pain and depression, induces sustained antidepressant-like effects in mouse models of chronic pain by blocking Tiam1-mediated maladaptive synaptic plasticity in ACC neurons. Our results reveal Tiam1 as a critical factor in the pathophysiology of chronic pain-induced depressive-like behaviors and the sustained antidepressant-like effects of ketamine.
| S-EPMC9753999 | biostudies-literature
Project description:BackgroundKetamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent.MethodsTo investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests.ResultsKetamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-β and NMDAR2-α subtypes as well as their downstream signaling proteins β-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus.ConclusionsThese findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.
| S-EPMC8088363 | biostudies-literature
Project description:One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear.Wistar-Kyoto rats were exposed to inescapable, uncontrollable footshocks. To evaluate learned helplessness behavior, we used an active avoidance task in a shuttle box equipped with an electrical grid floor. After helplessness assessment, we performed in vivo electrophysiological recordings first from ventral tegmental area dopaminergic (DA) neurons and second from accumbens neurons responsive to fimbria stimulation. Ketamine was injected and tested on helpless behavior and electrophysiological recordings.We show that ketamine is able to restore the integrity of a network by acting on the DA system and restoring synaptic dysfunction observed in stress-induced depression. We show that part of the antidepressant effect of ketamine is via the DA system. Indeed, injection of ketamine restores a decreased dopamine neuron population activity, as well as synaptic plasticity (long-term potentiation) in the hippocampus-accumbens pathway, via, in part, activation of D1 receptors.This work provides a unique systems perspective on the mechanisms of ketamine on a disrupted limbic system.
| S-EPMC4223010 | biostudies-literature
Project description:BackgroundClinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine.MethodsTwenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores.ResultsPatients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders.ConclusionsThese findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.
| S-EPMC3408548 | biostudies-literature
Project description:Triclosan, a widely used industrial and household agent, is present as an antiseptic ingredient in numerous products of everyday use, such as toothpaste, cosmetics, kitchenware, and toys. Previous studies have shown that human brain and animal tissues contain triclosan, which has been found also as a contaminant of water and soil. Triclosan disrupts heart and skeletal muscle Ca2+ signaling, damages liver function, alters gut microbiota, causes colonic inflammation, and promotes apoptosis in cultured neocortical neurons and neural stem cells. Information, however, on the possible effects of triclosan on the function of the hippocampus, a key brain region for spatial learning and memory, is lacking. Here, we report that triclosan addition at low concentrations to hippocampal slices from male rats inhibited long-term potentiation but did not affect basal synaptic transmission or paired-pulse facilitation and modified the content or phosphorylation levels of synaptic plasticity-related proteins. Additionally, incubation of primary hippocampal cultures with triclosan prevented both the dendritic spine remodeling induced by brain-derived neurotrophic factor and the emergence of spontaneous oscillatory Ca2+ signals. Furthermore, intra-hippocampal injection of triclosan significantly disrupted rat navigation in the Oasis maze spatial memory task, an indication that triclosan impairs hippocampus-dependent spatial memory performance. Based on these combined results, we conclude that triclosan exerts highly damaging effects on hippocampal neuronal function in vitro and impairs spatial memory processes in vivo.
| S-EPMC6275195 | biostudies-literature
Project description:Febrile seizures (FSs) in early life are significant risk factors of neurological disorders and cognitive impairment in later life. However, existing data about the impact of FSs on the developing brain are conflicting. We aimed to investigate morphological and functional changes in the hippocampus of young rats exposed to hyperthermia-induced seizures at postnatal day 10. We found that FSs led to a slight morphological disturbance. The cell numbers decreased by 10% in the CA1 and hilus but did not reduce in the CA3 or dentate gyrus areas. In contrast, functional impairments were robust. Long-term potentiation (LTP) in CA3-CA1 synapses was strongly reduced, which we attribute to the insufficient activity of N-methyl-D-aspartate receptors (NMDARs). Using whole-cell recordings, we found higher desensitization of NMDAR currents in the FS group. Since the desensitization of NMDARs depends on subunit composition, we analyzed NMDAR current decays and gene expression of subunits, which revealed no differences between control and FS rats. We suggest that an increased desensitization is due to insufficient activation of the glycine site of NMDARs, as the application of D-serine, the glycine site agonist, allows the restoration of LTP to a control value. Our results reveal a new molecular mechanism of FS impact on the developing brain.
| S-EPMC8347828 | biostudies-literature
Project description:Accumulating evidence underscores the utility of ketamine in treating severely treatment-resistant depressed patients. We investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. We gave 16 medication-free, major depressive disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging (MRI) to estimate their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS (post- minus pre-treatment) was significantly correlated with the pre-treatment volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several demographic and clinical variables, although the p value increased due to the reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants.
| S-EPMC4852551 | biostudies-literature
Project description:Hippocampal atrophy is one of the key changes in the brain implicated in the biology of depression. However, the precise molecular mechanism remains poorly understood due to a lack of biomarkers. In this research, we used behavioral experiments to evaluate anxiety and anhedonia levels in depressed rats using chronic unpredictable mild stress (CUMS) modeling. We also used isobaric tag for relative and absolute quantitation (iTRAQ) to identify the differentially expressed hippocampal proteins between depressed and normal rats. Bioinformatics analyses were also performed for a better understanding. The results showed that CUMS rats had higher anxiety and anhedonia levels than control rats, along with hippocampal lesions. Through iTRAQ and bioinformatics analyses, we found that ribosome proteins were significantly downregulated and Ras proteins exhibited a mixed change in the hippocampus of depressed rats. These findings suggest that the expression of hippocampal ribosome lesions and Ras proteins is significantly different in depressed rats than in control rats, providing new insights into the neurobiology of depression.
| S-EPMC6525853 | biostudies-literature
Project description:Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here, we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed with a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral--CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high-calorie diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines.
| S-EPMC2694409 | biostudies-literature
Project description:Experience-dependent synaptic plasticity is a fundamental feature of neural networks involved in the encoding of information, and the capability of synapses to express plasticity is itself activity-dependent. Here, we introduce a "low-frequency burst stimulation" protocol, which can readily induce both long-term potentiation (LTP) and long-term depression (LTD) at in vivo medial perforant path-dentate gyrus synapses. By varying stimulation parameters, we were able to build a stimulus-response map of synaptic plasticity as a LTP-LTD continuum. The response curve displayed a bidirectional shift toward LTP and LTD, depending on the degree and timing of neural activity of the basolateral amygdala. The range of this plastic modulation was also modified by past activity of the basolateral amygdala, suggesting that the amygdala can arrange its ability to regulate the dentate plastic responses. The effects of the BLA activation were replicated by stimulation of the lateral perforant path and, hence, BLA stimulation may recruit the lateral entorhinal cortex. These results represent a high-order dimension of heterosynaptic modulations of hippocampal synaptic plasticity.
| S-EPMC521145 | biostudies-literature