Severe mental disorders such as bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ) are characterized by reduced life expectancy, premature mortality and alterations of aging biomarkers, leading to hypothesize that they might be associated with accelerated cellular aging. We quantified the genetic overlap between severe mental disorders and a comprehensive set of aging biomarkers including multivariate longevity and healthy aging (mvAge), brain age gap (BAG), leucocyte telomere length (gLTL), mitochondrial DNA copy number and epigenetic age acceleration (gEAA) using cutting-edge methods, and evaluated their functional enrichment and suitability as drug targets. All disorders were negatively correlated with mvAge. Further, MDD correlated negatively with gLTL and positively with gEAA. We identified several pleiotropic variants, with nine genes (AC068490.2, ASIC2, CNNM2, FURIN, GPM6A, HS6ST3, RP5-1043L13.1, SORCS3 and SP4) containing variants shared between aging biomarkers and all disorders. Functional analyses with summary-data-based Mendelian randomization showed that increased expression of the druggable gene CRHR1 in the prefrontal cortex was associated with increased risk of MDD and BAG measures. Our findings suggest that shared heritability might contribute to reduced longevity and healthy aging in severe mental disorders and identify pleiotropic genes involved in synaptic function and metabolic processes related to micronutrients such as folate and magnesium.
Depression is a complex psychiatric disorder with multifaceted etiologies, and its underlying molecular mechanisms are incompletely elucidated. Although histidine trimeric nucleotide-binding protein 1 (HINT1) has been implicated in major depressive disorders (MDD), its precise role and regulatory mechanism remain unclear. This study investigated the role of HINT1 in depression-associated phenotypes. In mice subjected to chronic social defeat stress (CSDS), stress-susceptible individuals exhibited significant upregulation of HINT1 in the hippocampus and medial prefrontal cortex. Targeted overexpression of HINT1 in ventral hippocampus (vHip) demonstrated that HINT1 directly induced depressive-like behaviors, whereas its knockdown exerted a robust antidepressant-like effect. Pharmacological inhibition of HINT1 with the selective inhibitor Tryptamine guanosine carbamate (TpGc) in vHip also reversed behavioral deficits and normalized neuronal activity in the CSDS-exposed mice. Cell-type-specific analyses demonstrated that HINT1 overexpression in vHip GABAergic neurons, including somatostatin-positive (SST+) and parvalbumin-positive (PV+) subtypes, exacerbated depressive-like phenotypes and disrupted neuronal activity. Proteomics analysis identified that HINT1 overexpression in the vHip significantly upregulated the small ubiquitin-like modifier (SUMO) E3 ligases chromobox 4 (CBX4). Further overexpression of CBX4 in the GABAergic neurons of vHip induced depressive-like behaviors. Mechanistically, HINT1 interacted with and inhibited the phosphorylation of protein kinase C-β1 (PKCβ1), suppressing its downstream MEK1/2-ERK1/2 signaling and thereby increasing CBX4 levels. CBX4 promoted the SUMOylation of the glutamate N-methyl-D-aspartate receptor subunit 2 A (GluN2A) and affected its phosphorylation and trafficking. These findings demonstrated HINT1 as a key regulator of GABAergic signaling in vHip and highlighted its therapeutic potential for depression.
The NLRP3 inflammasome has emerged as a critical regulator in neuroinflammatory responses to various brain insults from traumatic, ischemic and neurodegenerative conditions, an effect almost exclusively attributed to microglial NLRP3. Here, we demonstrated that in the absence of changes in inflammatory factors IL-18, IL-1β and TNF-α, neuronal Nlrp3 knockout in hippocampus (nNlrp3-/-) improved long-term spatial memory performance, with increased synaptic proteins levels and enhanced amplitude of long-term potentiation at 4 weeks after traumatic brain injury (TBI), compared to wildtype littermates. Notably, the nNlrp3-/- mice out-performed microglia-specific knockout and global Nlrp3 knockout mice in cognition and synaptic function. We further identified that NLRP3 structurally and functionally directly interacted with the R1 subunit of N-methyl-D-aspartate receptor (NR1) in hippocampus after TBI. Accordingly, pharmacological inhibition of NLRP3 by MCC950 rescued the decrease in the NMDAR-gated calcium influx by LPS-stimulated hippocampal neurons while selective Nlrp3 knockout in hippocampal neurons partially reversed the decreased phosphorylation level of NR1 after TBI. Collectively, this study provides the first evidence that neuronal NLRP3 constitutes a non-inflammatory response to control synaptic plasticity and cognitive function via NR1-dependent non-inflammatory mechanism in TBI and thus broadens the central role of NLRP3 in neuronal adaptive mechanisms to include both microglial NLRP3-inflammation arm and the neuronal NLRP3-synaptic plasticity arm.
Adult hippocampal neurogenesis (AHN) occurs throughout lifespan of humans and rodents and is correlated with memory performance and cognitive plasticity. In Alzheimer’s disease (AD), AHN is impeded, while the molecular basis behind this impairment remains to be elucidated. Here we identified Breast carcinoma amplified sequence 2 (BCAS2), a core component of the CDC5L/Prp19 spliceosome complex, regulating AHN in AD. Using Bcas2 conditional knockout mice, AD mouse model APP/PS1 mice, established mouse primary adult neural stem cells and single cell sequencing, we demonstrate that BCAS2 replacement in adult mouse hippocampus promotes NSC activation and differentiation to neuron, restore AHN and relevant memory deficits through BDNF/TrkB signaling. Our findings corroborate the significance of AHN in AD and reveal the possible therapeutic potential of targeting BCAS2 in neurodegeneration.
Studying the neural circuits that mediate context-induced fear memory retrieval is of importance to develop new therapeutic approaches to prevent post-traumatic stress disorder relapse. The basolateral amygdala (BLA) is crucial for context-induced retrieval of fear memory. Previous studies indicate that projection neurons from the ventral hippocampus CA1 (vCA1) to the BLA (vCA1-BLA neurons) mediate context-induced retrieval of fear memory. However, it remains unclear whether other projection neurons to the BLA are involved in context-induced retrieval of fear memory and how they interact with vCA1-BLA neurons. Our findings indicate that the postrhinal cortex (POR) to the BLA (POR-BLA) neurons are also involved in context-induced retrieval of fear memory. These neurons innervate the same BLA neurons as vCA1-BLA neurons and participate in fear memory retrieval. These results suggest that two different projection neurons of POR-BLA and vCA1-BLA innervate on the same BLA neurons and POR-BLA neurons and vCA1-BLA neuron contribute to fear memory retrieval. These findings provide new insights into the neural mechanisms underlying fear memory retrieval.
