Chronically altered NMDAR signaling in epilepsy mediates comorbid depression

Abstract

Depression is the most common psychiatric comorbidity of epilepsy. However, the molecular pathways underlying this association remain unclear. The NMDA receptor (NMDAR) may play a role in this association, as its downstream signaling has been shown to undergo long-term changes following excitotoxic neuronal damage. To study this pathway, we used an animal model of fluoxetine-resistant epilepsy-associated depression (EAD). We determined the molecular changes associated with the development of depressive symptoms and examined their response to various combinations of fluoxetine and a selective neuronal nitric oxide synthase inhibitor, 7-nitroindazole (NI). Depressive symptoms were determined using the forced swim test. Furthermore, expression and phosphorylation levels of markers in the ERK/CREB/ELK1/BDNF/cFOS pathway were measured to determine the molecular changes associated with these symptoms. Finally, oxidative stress markers were measured to more clearly determine the individual contributions of each treatment. While chronic fluoxetine (Flxc) and NI were ineffective alone, their combination had a statistically significant synergistic effect in reducing depressive symptoms. The development of depressive symptoms in epileptic rats was associated with the downregulation of ERK2 expression and ELK1 and CREB phosphorylation. These changes were exactly reversed upon Flxc + NI treatment, which led to increased BDNF and cFOS expression as well. Interestingly, ERK1 did not seem to play a role in these experiments. NI seemed to have augmented Flxc’s antidepressant activity by reducing oxidative stress. Our findings suggest NMDAR signaling alterations are a major contributor to EAD development and a potential target for treating conditions associated with underlying excitotoxic neuronal damage.

Mechanism of ERK/CREB pathway in pain and analgesia

“…In cerebral ischemia rats model, the levels of p-ERK and p-CREB were significantly decreased, the activation of ERK/CREB pathway was significantly inhibited, and the expression of pro-inflammatory cytokine IL-6 and TNF-α was increased in post-stroke depression through sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), western blot and Elisa experiments ( Yin Q. et al, 2021 ). It was also found in epileptic rats that the development of depression comorbidity was related to the decrease of ERK2 expression and the inhibition of CREB phosphorylation ( Sadeghi et al, 2021 ). However, endogenous opioid drugs lead to depression through multiple mechanisms including preventing the ERK/CREB pathway from being activated.…”

“…It was also found in epileptic rats that the development of depression comorbidity was Some strategies for treating pain while avoiding cognitive impairment. Zhen et al 10.3389/fnmol.2023.1156674 Frontiers in Molecular Neuroscience 05 frontiersin.org related to the decrease of ERK2 expression and the inhibition of CREB phosphorylation (Sadeghi et al, 2021). However, endogenous opioid drugs lead to depression through multiple mechanisms including preventing the ERK/CREB pathway from being activated.…”

The Dual Dose-Dependent Effects of Corticosterone on Hippocampal Cell Apoptosis After Traumatic Brain Injury Depend on the Activation Ratio of Mineralocorticoid Receptors to Glucocorticoid Receptors

“…In addition, crosstalk between components of apoptosis-related pathways is very common. For instance, CREB has been reported to be activated by several signaling pathways after TBI, including the IP3K/Akt, cyclic AMP-dependent protein kinase/protein kinase A, and the MAPK/Erk pathways (Su et al, 2017;Schreiber et al, 2020;Sadeghi et al, 2021). However, the effect of a given signaling pathway on CREB activation remains controversial because the overall CREB activation level is generally determined by interactions of multiple signaling pathways, not a single pathway.…”

Low-cost platform for multi-animal chronic local field potential video monitoring with graphical user interface (GUI) for seizure detection and behavioral scoring

“…Categorization of the behavioral severity of seizures is critical for determining disease stage – for example, chronic epilepsy is defined by the occurrence of two or more behavioral seizures. In addition to studies of epilepsy, video-neurophysiology recordings are becoming widely used in rodent studies of other pathologies that are sometimes comorbid with epileptiform activity including depression (Sadeghi et al, 2021), Alzheimer’s Disease (Harris et al, 2010; reviewed in Vossel et al, 2017), and autism (Lewis et al, 2018; Eisenberg et al, 2021; reviewed in Specchio et al, 2022).…”