Molecular Psychiatry最新文献

Developmental changes in prefrontal cortex (PFC) excitatory (glutamatergic, Glu) and inhibitory (gamma- aminobutryic acid, GABA) neurotransmitter balance (E:I) have been identified during human adolescence, potentially reflecting a critical period of plasticity that supports the maturation of PFC-dependent cognition. Animal models implicate increases in dopamine (DA) in regulating changes in PFC E:I during critical periods of development, however, mechanistic relationships between DA and E:I have not been studied in humans. Here, we used high field (7T) echo planar imaging (EPI) in combination with Magnetic Resonance Spectroscopic Imaging (MRSI) to assess the role of basal ganglia tissue iron—reflecting DA neurophysiology—in longitudinal trajectories of dorsolateral PFC Glu, GABA, and their relative levels (Glu:GABA) and working memory performance from adolescence to adulthood in 153 participants (ages 10–32 years old, 1–3 visits, 272 visits total). Using generalized additive mixed models (GAMMs) that capture linear and non-linear developmental processes, we show that basal ganglia tissue iron increases during adolescence, and Glu:GABA is biased towards heightened Glu relative to GABA early in adolescence, decreasing into adulthood. Critically, variation in basal ganglia tissue iron was linked to different age-related trajectories in Glu:GABA and working memory. Specifically, individuals with higher levels of tissue iron showed a greater degree of age-related declines in Glu and Glu:GABA, resulting in lower Glu relative to GABA (i.e., higher GABA relative to Glu) in young adulthood. Variation in tissue iron additionally moderated working memory trajectories, as higher levels of tissue iron were associated with steeper age-related improvements and better performance into adulthood. Our results provide novel evidence for a model of critical period plasticity whereby individual differences in DA may be involved in fine-tuning PFC E:I and PFC-dependent cognitive function at a critical transition from adolescence into adulthood.

We want to thank Pappagallo et al. [1] for their commentary about our recent article [2] which delved into the pharmacodynamic divergence of (R)- and (S)-methadone. Based on our experimental findings, we concluded that (S)-methadone, like (R,S)-methadone and (R)-methadone, is an agonist at the μ opioid receptor (MOR) but with much lower potency. Importantly, (S)-methadone exhibits a unique pharmacodynamic effect by acting as a MOR antagonist when MOR is complexed with the galanin 1 receptor (Gal₁R). Since our previous studies showed that MOR-Gal₁R heteromers mediate the dopaminergic effects of opioids [3], this specific antagonist property of (S)-methadone explains the low efficacy of (R,S)-methadone at activating the dopaminergic system and at eliciting euphoric effects. Accordingly, at sufficient doses/concentrations, (S)-methadone counteracts the locomotor activating and dopamine releasing effects of (R)-methadone. While (S)-methadone may act as an antagonist at the N-methyl-D-aspartate receptor (NMDAR), the drug concentration needed to achieve this effect is higher than what is needed to interact with MORs in vivo. As such, we stated “The currently assumed role of NMDAR blockade in the purported antidepressant effects of (S)-MTD should be reframed in the context of its MOR agonistic properties.” Pappagallo et al. [1] disagreed with this statement. We address their comments below.

Our hot plate findings are a key component of the MOR agonist effects of (S)-methadone, but they are not the only evidence we provided. (S)-methadone also produces hypothermia and partial catalepsy [2], two prototypical effects of MOR agonists in rats. We also used [³⁵S]GTPγS binding in rat brain sections to show that (S)-methadone increases GPCR activity in the striatum at a concentration that does not interact with NMDARs, and that this response was blocked by pretreatment with the preferential MOR antagonist naltrexone. Since the [³⁵S]GTPγS assay is specific to GPCRs and does not involve ion channel activation or inhibition, we conclude that this activation is mediated by opioid receptors, most likely MORs. We also used BRET in transfected cells to show that (S)-methadone acts as an agonist at MOR. Finally, we found that 30 mg/kg (S)-methadone, a dose used to produce antidepressant-like effects in rats (10–40 mg/kg) [4, 5], occupies nearly 80% of striatal MORs without significant occupancy of NMDARs, using an assay which has previously shown occupancy by ketamine at these receptors [6]. Thus, we used diverse and independent approaches to confirm that (S)-methadone binds to and activates MORs at doses/concentrations that do not bind NMDARs in vivo.

Postpartum psychosis (PP) is a severe psychiatric disorder–with limited data or consensus on diagnostic criteria and clinical presentation–that affects thousands of people each year. The Massachusetts General Hospital Postpartum Psychosis Project (MGHP3) was established to: 1) describe the phenomenology of PP, and 2) identify genomic and clinical predictors in a large cohort. Results thus far point to a richer understanding of the heterogeneity and complexity of this often-misunderstood illness and its nature over time. Data are collected from those who experienced PP within 6 months of delivery and within the 10 years prior to the MGHP3 interview. Participants provide information via the Mini International Neuropsychiatric Interview for Psychotic Disorders Studies (MINI-PDS), MGHP3© Questionnaire (including assessment of episode onset, duration, symptoms, and treatment received), and other relevant history. This retrospective study uses validated diagnostic tools to evaluate psychiatric history across participants’ lifetimes. Descriptive statistics (e.g., median values, frequencies) were conducted to describe the phenomenology of PP. As of November 3, 2022, 248 participants with histories of at least one episode of PP completed the MGHP3 interview. Most participants met criteria for Bipolar I Disorder with psychotic features (71.8%). During PP episode(s), participants reported odd beliefs or delusions (87.6%), persecutory delusions (75.2%), ideas of reference (55.8%), and visual (52.3%) and/or auditory (48.1%) hallucinations. The median time between delivery and symptom onset was 10 days (SD = 43.72). Most participants reported receiving medication (93.0%) and/or psychotherapy (65.9%). This report describes findings regarding the phenomenology of postpartum psychosis among the MGHP3 cohort, the largest cohort with validated PP studied to date. This ongoing effort to refine the phenotype of PP and to delineate underlying genetic determinants of the disorder will contribute to an enhanced understanding of this serious illness. It also underscores areas for further rigorous assessment using other research methods and sets the stage for translational reproductive neuroscience – including ongoing analyses of neuroimaging and genetic data from the MGHP3 cohort.

The delta opioid receptor (DOP) is a promising target for novel antidepressants due to its potential for rapid action with minimal adverse effects; however, the functional mechanism underlying acute antidepressant actions remains elusive. We report that subcutaneous injection of the selective DOP agonist KNT-127 reduced immobility in the forced swimming test, and that this antidepressant-like response was reversed by intracerebroventricular injection of the selective mechanistic (or mammalian) target of rapamycin (mTOR) inhibitor rapamycin or the phosphatidylinositol-3 kinase (PI3K) inhibitor LY294002. KNT-127 also alleviated social avoidance and reduced sucrose consumption (anhedonia) among chronic vicarious social defeat stress model mice, which were similarly reversed by PI3K and mTOR inhibitors. In addition, KNT-127 increased phosphorylation levels of the mTOR signaling-related proteins Akt and p70S6 kinase in medial prefrontal cortex as revealed by immunoblotting. In the forced swimming test, a microinfusion of KNT-127 and another DOP agonist SNC80 in the infralimbic prefrontal cortex (IL-PFC) attenuated the immobility, which were blocked by rapamycin and LY294002. Perfusion of KNT-127 onto IL-PFC slices increased miniature excitatory postsynaptic current frequency and reduced miniature inhibitory postsynaptic current frequency in pyramidal neurons as measured by whole-cell patch-clamping, and both responses were reversed by rapamycin. Imaging of brain slices from transgenic mice with DOP-promoter-driven green fluorescent protein revealed that most DOPs were expressed in parvalbumin-positive interneurons in the IL-PFC. These findings suggest that DOP agonists exert antidepressant-like actions by suppressing GABA release from parvalbumin-positive interneurons via the PI3K–Akt–mTORC1–p70S6 kinase pathway, thereby enhancing IL-PFC pyramidal neuron excitation.

Background/objectives

Dysregulation of molecular pathways associated with mechanistic target of rapamycin (mTOR) and elevated rates of neurodevelopmental disorders are implicated in the genetic syndromes neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC), fragile X syndrome (FXS), and Noonan syndrome (NS). Given shared molecular and clinical features, understanding convergent and divergent implications of these syndromes on brain development may offer unique insights into disease mechanisms. While an increasing number of studies have examined brain volumes in these syndromes, the effects of each syndrome on global and subcortical brain volumes are unclear. Therefore, the aim of the current study was to conduct a systematic review and meta-analysis to synthesize existing literature on volumetric brain changes across TSC, FXS, NF1, and NS. Study outcomes were the effect sizes of the genetic syndromes on whole brain, gray and white matter, and subcortical volumes compared to typically developing controls.

Subjects/methods

We performed a series of meta-analyses synthesizing data from 23 studies in NF1, TSC, FXS, and NS (pooled N = 1556) reporting whole brain volume, gray and white matter volumes, and volumes of subcortical structures compared to controls.

Results

Meta-analyses revealed significantly larger whole brain volume, gray and white matter volumes, and subcortical volumes in NF1 compared to controls. FXS was associated with increased whole brain, and gray and white matter volumes relative to controls, but effect sizes were smaller than those seen in NF1. In contrast, studies in NS indicated smaller whole brain and gray matter volumes, and reduced subcortical volumes compared to controls. For individuals with TSC, there were no significant differences in whole brain, gray matter, and white volumes compared to controls. Volumetric effect sizes were not moderated by age, sex, or full-scale IQ.

Conclusions

This meta-analysis revealed that dysregulation of mTOR signaling across pre- and post-natal periods of development can result in convergent and divergent consequences for brain volume among genetic syndromes. Further research employing advanced disease modeling techniques with human pluripotent stem cell-derived in vitro models is needed to further refine our understanding of between and within syndrome variability on early brain development and identify shared molecular mechanisms for the development of pharmaceutical interventions.

Cortical hypometabolism on FDG-PET is a well-established neuroimaging biomarker of cognitive impairment in Parkinson’s disease (PD), but its pathophysiologic origins are incompletely understood. Cholinergic basal forebrain (cBF) degeneration is a prominent pathological feature of PD-related cognitive impairment and may contribute to cortical hypometabolism through cholinergic denervation of cortical projection areas. Here, we investigated in-vivo associations between subregional cBF volumes on 3T-MRI, cortical hypometabolism on [¹⁸F]FDG-PET, and cognitive deficits in a cohort of 95 PD participants with varying degrees of cognitive impairment. We further assessed the spatial correspondence of the cortical pattern of cBF-associated hypometabolism with the pattern of cholinergic denervation in PD as assessed by [¹⁸F]FEOBV-PET imaging of presynaptic cholinergic terminal density in a second cohort. Lower volume of the cortically-projecting posterior cBF, but not of the anterior cBF, was significantly associated with extensive neocortical hypometabolism [p(FDR) < 0.05], which mediated the association between cBF atrophy and cognitive impairment (mediated proportion: 43%, p < 0.001). In combined models, posterior cBF atrophy explained more variance in cortical hypometabolism (R² = 0.26, p < 0.001) than local atrophy in the cortical areas themselves (R² = 0.16, p = 0.01). Topographic correspondence analysis with the [¹⁸F]FEOBV-PET pattern revealed that cortical areas showing most pronounced cBF-associated hypometabolism correspond to those showing most severe cholinergic denervation in PD (Spearman’s ρ = 0.57, p < 0.001). In conclusion, posterior cBF atrophy in PD is selectively associated with hypometabolism in denervated cortical target areas, which mediates the effect of cBF atrophy on cognitive impairment. These data provide first-time in-vivo evidence that cholinergic degeneration represents a principle pathological correlate of cortical hypometabolism underlying cognitive impairment in PD.

Dysfunctional glial cells play a pre-eminent role in schizophrenia pathophysiology. Post-mortem studies have provided evidence for significantly decreased glial cell numbers in different brain regions of individuals with schizophrenia. Reduced glial cell numbers are most pronounced in oligodendroglia, but reduced astrocyte cell densities have also been reported. This review highlights that oligo- and astroglial deficits are a key histopathological feature in schizophrenia, distinct from typical changes seen in neurodegenerative disorders. Significant deficits of oligodendrocytes in schizophrenia may arise in two ways: (i) demise of mature functionally compromised oligodendrocytes; and (ii) lack of mature oligodendrocytes due to failed maturation of progenitor cells. We also analyse in detail the controversy regarding deficits of astrocytes. Regardless of their origin, glial cell deficits have several pathophysiological consequences. Among these, myelination deficits due to a reduced number of oligodendrocytes may be the most important factor, resulting in the disconnectivity between neurons and different brain regions observed in schizophrenia. When glial cells die, it appears to be through degeneration, a process which is basically reversible. Thus, therapeutic interventions that (i) help rescue glial cells (ii) or improve their maturation might be a viable option. Since antipsychotic treatment alone does not seem to prevent glial cell loss or maturation deficits, there is intense search for new therapeutic options. Current proposals range from the application of antidepressants and other chemical agents as well as physical exercise to engrafting healthy glial cells into brains of schizophrenia patients.

Background

Depression in pregnancy can increase vulnerability for psychiatric disorders in the offspring, likely via the transfer of heightened maternal cortisol and cytokines to the in-utero environment. However, the precise cellular and molecular mechanisms, are largely unclear. Animal studies can represent this complex pathophysiology at a systemic level but are expensive and ethically challenging. While simpler, in vitro models offer high-throughput opportunities. Therefore, this systematic review integrates findings of in vitro models relevant to depression in pregnancy, to generate novel hypotheses and targets for intervention.

Methods

The systematic analysis covered studies investigating glucocorticoid or cytokine challenges on placental or foetal neural progenitor cells (NPCs), with or without co-treatment with sex hormones.

Results

Of the 50 included studies, 11 used placental cells and 39 NPCs; surprisingly, only one used a combination of oestrogen and cortisol, and no study combined placental cells and NPCs. In placental cells, cortisol or cytokines decreased nutrient transporter expression and steroidogenic enzyme activity, and increased cytokine production. NPCs exhibited decreases in proliferation and differentiation, via specific molecular pathways, namely, inhibition of hedgehog signalling and activation of kynurenine pathway. In these cells, studies also highlighted epigenetic priming of stress and inflammatory pathways.

Conclusions

Overall, results suggest that stress and inflammation not only detrimentally impact placental regulation of nutrients and hormones to the foetus, but also activate downstream pathways through increased inflammation in the placenta, ultimately eliciting adverse effects on foetal neurogenesis. Future research should investigate how sex hormones regulate these mechanisms, with the aim of developing targeted therapeutic approaches for depression in pregnancy.

Dyrk1A deficiency is linked to various neurodevelopmental disorders, including developmental delays, intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of Dyrk1a in mice reportedly leads to ASD-related phenotypes. However, the key pathological mechanisms remain unclear and human DYRK1A mutations remain uncharacterized in mice. Here, we generated and studied Dyrk1a-knockin mice carrying a human ASD patient mutation (Ile48LysfsX2; Dyrk1a-I48K mice). These mice display severe microcephaly, social and cognitive deficits, dendritic shrinkage, excitatory synaptic deficits, and altered phospho-proteomic patterns enriched for multiple signaling pathways and synaptic proteins. Early chronic lithium treatment of newborn mutant mice rescues the brain volume, behavior, dendritic, synaptic, and signaling/synapse phospho-proteomic phenotypes at juvenile and adult stages. These results suggest that signaling/synaptic alterations contribute to the phenotypic alterations seen in Dyrk1a-I48K mice, and that early correction of these alterations by lithium treatment has long-lasting effects in preventing juvenile and adult-stage phenotypes.

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer’s Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10⁻⁸) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10⁻⁶). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.