Stress-induced reduction of Na ⁺ /H ⁺ exchanger isoform 1 promotes maladaptation of neuroplasticity and exacerbates depressive behaviors

Abstract

Major depression disorder (MDD) is a neuropsychiatric disorder characterized by abnormal neuronal activity in specific brain regions. A factor that is crucial in maintaining normal neuronal functioning is intracellular pH (pHi) homeostasis. In this study, we show that chronic stress, which induces depression-like behaviors in animal models, down-regulates the expression of the hippocampal Na + /H + exchanger isoform 1, NHE1, a major determinant of pHi in neurons. Knockdown of NHE1 in CA1 hippocampal pyramidal neurons leads to intracellular acidification, promotes dendritic spine loss, lowers excitatory synaptic transmission, and enhances the susceptibility to stress exposure in rats. Moreover, E3 ubiquitin ligase cullin4A may promote ubiquitination and degradation of NHE1 to induce these effects of an unbalanced pHi on synaptic processes. Electrophysiological data further suggest that the abnormal excitability of hippocampal neurons caused by maladaptation of neuroplasticity may be involved in the pathogenesis of this disease. These findings elucidate a mechanism for pHi homeostasis alteration as related to MDD.

The gene expression patterns as surrogate indices of pH in the brain

“…This effect was speculated to be due to increased excitotoxicity caused by ASIC1a activation, as acidic treatment induced an ASIC1a-dependent increase in intracellular Ca 2+ concentration in dendritic spines ( 82 ). Furthermore, a recent study showed that intracellular acidification in hippocampal neurons promotes dendritic spine loss and increases stress vulnerability in depression model rats ( 83 ). Therefore, extracellular and intracellular acidification may lead to spine impairments at the molecular and cellular levels that may be involved in psychiatric consequences.…”

Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment

“…These results suggest that brain lactate is an important regulator of tissue pH ( Prabakaran et al, 2004 ), although we cannot exclude the possibility that other factors, such as neuronal activity-regulated production of carbon dioxide, another metabolic acid, may also contribute to changes in brain pH ( Chesler, 2003 ; Zauner et al, 1995 ). Furthermore, the observed pH changes may be due to the dysregulation of neuronal ( Li et al, 2022 ; Pruett et al, 2023 ) and astroglial ( Theparambil et al, 2020 ) mechanisms of H + ion transport and buffering to regulate intracellular and extracellular pH homeostasis, which should be investigated in our model animals.…”

CA1i pyramidal neurons mediate the role of NMDA receptor subunit GluN3A in depressive behavior and D-serine anti-depression

“…A previous study by Lee et al also demonstrated that GluN3A knockout mice exhibited lower neuronal c-Fos expression and decreased phosphorylation levels of CaMKII in the olfactory bulb during olfactory discrimination tasks[69]. Li et al also reported that activity inhibition of CA1 pyramidal neurons could facilitate the depressive behaviors induced by stress[50]. On the other hand, a recent study by Su et al indicated that the increase CA1 neuronal activity, which induced by GluN2A inhibition, was essential for the rapid antidepressive effect of ketamine[22].…”

“…The structural and functional abnormalities of hippocampus have been recognized as important pathophysiological bases in depression and targets involved in the efficacy of antidepressant therapy[45–47]. Extensive alterations in the number and morphology of neurons and synapses, as well as LTP and long-term depression (LTD) response in hippocampus are reported in depressive patients and animal models[48–50]. The restoration of hippocampal abnormalities is consistent with the amelioration of depressive symptoms after chronic antidepressant treatment[15].…”