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3D reconstruction of white matter tracts where we observed a significant interaction between EAAT2-181A > C genotype and ACE on axial diffusivity. Voxel of significant effect surviving a significant threshold of p < 0.05 corrected for multiple comparison is shown on a 3D T1-weighted image
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Glutamate is the principal excitatory neurotransmitter in the central nervous system. In mature brains, it is critically involved in neuroplasticity and, at high levels, neurotoxicity. The concentrations of glutamate in the extracellular space are maintained at low physiological levels by molecular glutamate transporters (excitatory amino acid tran...
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... Moreover, DNA methylation (DNAm) of DDR1 was found to be associated with DDR1 gene expression in the blood and brain of patients with schizophrenia (SZ) [8] and in the brain of patients with bipolar disorder (BD) [7]. Overall, these results are consistent with the findings of white matter structure abnormalities [9][10][11] and changes in the expression of myelin-related genes [12] found in the brains of patients with BD. ...
... Environmental factors can influence the DNAm of myelin genes and, as a consequence, the myelination process [22]. Taken together, these findings suggest that changes in DDR1 DNAm in the brain may be more closely related to oligodendrocyte dysfunction and abnormalities in white matter structure, which are present in patients with BD [9][10][11], than to altered pathways leading to SB. ...
Altered DNA methylation (DNAm) patterns of discoidin domain receptor 1 (DDR1) have been found in the blood and brain of patients with schizophrenia (SCZ) and the brain of patients with bipolar disorder (BD). Childhood trauma (CT) is associated with changes in DNAm that in turn are related to suicidal behavior (SB) in patients with several psychiatric disorders. Here, using MassARRAY® technology, we studied 128 patients diagnosed with BD in remission and 141 healthy controls (HCs) to compare leukocyte DDR1 promoter DNAm patterns between patients and HCs and between patients with and without SB. Additionally, we investigated whether CT was associated with DDR1 DNAm and mediated SB. We found hypermethylation at DDR1 cg19215110 and cg23953820 sites and hypomethylation at cg14279856 and cg03270204 sites in patients with BD compared to HCs. Logistic regression models showed that hypermethylation of DDR1 cg23953820 but not cg19215110 and CT were risk factors for BD, while cg14279856 and cg03270204 hypomethylation were protective factors. In patients, CT was a risk factor for SB, but DDR1 DNAm, although associated with CT, did not mediate the association of CT with SB. This is the first study demonstrating altered leukocyte DDR1 promoter DNAm in euthymic patients with BD. We conclude that altered DDR1 DNAm may be related to immune and inflammatory mechanisms and could be a potential blood biomarker for the diagnosis and stratification of psychiatric patients.
... 8 External events not only have the potential to directly trigger emotional changes, but more importantly, they may disrupt neurotransmitter systems, 49 leading to a level of mood cycling that aligns with the manifestation of psychiatric disorders, such as BD. 50 Report from Science have confirmed that neurotransmitter transitions in the adult brain can be achieved through natural sensory stimuli, further regulating behavior. 51 And, the kindling hypothesis of mood disorders suggests that this process may become increasingly spontaneous. ...
推荐引用方式（在期刊接受之前）：Zhang, Gui,Zhong, Yuan.(2023).A Dynamic Process Model of Bipolar Disorder States Switching Based on the Salience Network.中国科学院科技论文预发布平台.doi:10.12074/202308.00210V2
（已投稿期刊）
... The WM tracts involved include inferior and superior longitudinal fasciculus and the inferior fronto-occipital fasciculus. This suggest that G/G homozygotes are vulnerable to stress as a consequence of an excess of free Glu (Poletti et al., 2019). Moreover, the same group reported lower fractional anisotropy (FA) in bilateral frontal WM tracts, lower gray matter (GM), and higher BOLD fMRI neural responses to emotional stimuli in medial prefrontal cortex (mPFC) in AA risk genotype of the Homer rs7713917, along with long term effects of lithium on WM structure (Benedetti et al., 2018). ...
The monoamine hypothesis has dominated research on the pathophysiology of mood disorders as well as the development of therapeutic drugs by over half a century. Nowadays a change of perspective is taking place. The glutamate system is increasingly implicated in the pathophysiology of mood disorders. The evidence spans from animal, post-mortem, imaging, pharmacological and genome-wide association studies. Bipolar disorder has been recently re-conceptualized as a synaptic plasticity-related disorder rather than simply as a result of deficits or excesses in individual neurotransmitters. A paradigm shift from a monoamine hypothesis to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the research for new drugs and therapies. In this review we summarize data from clinical and pre-clinical studies that have addressed glutamatergic alterations in bipolar disorder. Along with an in-depth discussion of glutamatergic alterations in bipolar disorder, we also report available data on the neuroprotective and neuroplastic potential of the classic mood stabilizers, ketamine, and psychedelics. The glutamatergic mechanisms underlying the efficacy of these drugs are described and discussed.
... A negative association between mI levels and FA has been reported both in patients with schizophrenia and healthy controls (Chiappelli et al., 2015). Finally, Glu-excitotoxicity can affect also oligodendrocytes and myelin (Matute et al., 2007) and, indeed, genetic variants affecting glutamatergic neurotransmission associate with the disruption of WM in BD (Poletti et al., 2019a). ...
Bipolar disorder (BD) is associated with alterations in white matter (WM) microstructure, glutamatergic neurotransmission, and glia activity. Previous studies showed higher concentrations of glutamate (Glu), glutamate+glutamine (Glx), and reduced N-acetyl-aspartate (NAA) in BD. We investigated brain concentrations of Glu, Glx, NAA, mI as indirect marker of microglia activation, and Glx/NAA ratio as index of neuronal damage through ¹H-MR, and WM integrity with Tract-Based Spatial Statistics in 93 depressed BD patients and 58 healthy controls (HC).
We tested for linear effects of cited spectroscopic metabolites on DTI measures of WM integrity with general linear models for each group, then performing a conjunction analysis of Glx/NAA and mI concentration on the same measures. Statistical analyses (whole sample) revealed higher concentration of Glx/NAA, Glx and mI in BD patients compared to HC, and a positive association between mI and the ratio. DTI analyses (87 BD and 35 HC) showed a significant association of Glx/NAA ratio, and mI with WM microstructure. Conjunction analysis revealed a joint negative association between Glx/NAA and mI with fractional anisotropy.
This is the first study showing an association between brain metabolites involved in neuronal damage, and glial activation and the alterations in WM consistently reported in BD.
... Therefore, it has been suggested that glutamate excitotoxicity can lead to neuronal death and axon demyelination (Dias, 2012;Kim et al., 2010;Matute et al., 2001;Pitt et al., 2000). To the best of our knowledge, only a few studies have investigated the link between abnormal glutamate levels and WM damage in neuropsychiatric disorders (Bustillo et al., 2017;León-Ortiz et al., 2020;Poletti et al., 2019a;Reid et al., 2016). ...
Neuropsychiatric disorders including generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ) have been considered distinct categories of diseases despite their overlapping characteristics and symptomatology. We aimed to provide an in-depth review elucidating the role of glutamate/Glx and white matter (WM) abnormalities in these disorders from a transdiagnostic perspective. The PubMed online database was searched for studies published between 2010 and 2021. After careful screening, 401 studies were included. The findings point to decreased levels of glutamate in the Anterior Cingulate Cortex in both SZ and BD, whereas Glx is elevated in the Hippocampus in SZ and MDD. With regard to WM abnormalities, the Corpus Callosum and superior Longitudinal Fascicle were the most consistently identified brain regions showing decreased fractional anisotropy (FA) across all the reviewed disorders, except GAD. Additionally, the Uncinate Fasciculus displayed decreased FA in all disorders, except OCD. Decreased FA was also found in the inferior Longitudinal Fasciculus, inferior Fronto-Occipital Fasciculus, Thalamic Radiation, and Corona Radiata in SZ, BD, and MDD. Decreased FA in the Fornix and Corticospinal Tract were found in BD and SZ patients. The Cingulum and Anterior Limb of Internal Capsule exhibited decreased FA in MDD and SZ patients. The results suggest a gradual increase in severity from GAD to SZ defined by the number of brain regions with WM abnormality which may be partially caused by abnormal glutamate levels. WM damage could thus be considered a potential marker of some of the main neuropsychiatric disorders.
... Brain function also changes with exposure to ACEs. Stress from ACEs interferes with the brain's regulation of the neurotransmitter glutamate, and interacts with the genes that manage the release of glutamate to alter the structure of white matter in the brain (Poletti et al., 2019). ...
... Healthy controls Recent studies based upon neuroimaging, gene expression or both have demonstrated that abnormalities in white matter structure [1][2][3] and changes in oligodendrocyte gene expression [4] are present in the brains of patients with bipolar disorder (BD). Likewise, other studies have shown similar results in schizophrenia (SZ) [5][6][7][8][9][10]. ...
Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.
... The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2) are Na + transporters that are mainly expressed in glia and regulate glutamatergic transmission through the uptake of glutamate (mostly EAAT2) and aspartate; the glutamatergic transmission is increasingly recognised as being important in mental disorders, like schizophrenia, bipolar and other mood disorders (Parkin et al., 2018). Their risk genes EAAT1 rs2731880 T/T and EAAT2-181A > C (SLC1A2 gene) (rs4354668) were investigated in BD patients in two studies by the same group Poletti et al., 2019). The first was a FC study and showed reduced FC in risk gene carriers in the right hemisphere, between the amygdala and the anterior subgenual cingulate cortex during a face-matching task, then also during emotional processing of faces . ...
There is evidence of genetic polymorphism influences on brain structure and function, genetic risk in bipolar disorder (BD), and neuroimaging correlates of BD. How genetic influences related to BD could be reflected on brain changes in BD has been efficiently reviewed in a 2017 systematic review. We aimed to confirm and extend these findings through a Preferred Reporting Items for Systematic reviews and Meta-Analyses-based systematic review. Our study allowed us to conclude that there is no replicated finding in the timeframe considered. We were also unable to further confirm prior results of the BDNF gene polymorphisms to affect brain structure and function in BD. The most consistent finding is an influence of the CACNA1C rs1006737 polymorphism in brain connectivity and grey matter structure and function. There was a tendency of undersized studies to obtain positive results and large, genome-wide polygenic risk studies to find negative results in BD. The neuroimaging genetics in BD field is rapidly expanding.
... Impairments in connectivity between the neocortex and the amygdala and in particular GLAST dysfunction is seen in both animal models of BD and humans with BD (Poletti et al., 2018). What is more, white matter GLT-1 expression is particularly sensitive to early life stressors and reductions in GLT-1 are observed in BD populations (Poletti et al., 2019(Poletti et al., , 2018. Interestingly, the gene for GLT-1, SLC1A2, shows considerable Table adapted from Bao and Swaab, 2011. ...
Astroglial cells are the most abundant cell type in the mammalian brain. They are implicated in almost every aspect of brain physiology, including maintaining homeostasis, building and maintaining the blood brain barrier, and the development and maturation of neuronal networks. Critically, astroglia also express receptors for gonadal sex hormones, respond rapidly to gonadal hormones, and are able to synthesize hormones. Thus, they are positioned to guide and mediate sexual differentiation of the brain, particularly neuronal networks in typical and pathological conditions. In this review, we describe astroglial involvement in the organization and development of the brain, and consider known sex differences in astroglial responses to understand how astroglial cell-mediated organization may play a role in forebrain sexual dimorphisms in human populations. Finally, we consider how sexually dimorphic astroglial responses and functions in development may lead to sex differences in vulnerability for neuropsychiatric disorders.
... Aberrant expression of SLC1A3 has been associated with neurological disorders, including hypoxic-ischaemic brain damage, [12][13][14] Alzheimer's disease (AD), 15 episodic ataxia, 16 hemiplegia, 17 epilepsy, 18 schizophrenia 19,20 and emotional and cognitive abnormalities. [21][22][23] SLC1A3 has also recently been shown to be involved in tumour metabolism and tumour progression. 24 L-asparaginase targets the limiting metabolite for tumour cell proliferation under hypoxia, and SLC1A3 overexpression contributes to L-asparaginase resistance in solid tumours. ...
Gastric cancer is a major cause of mortality worldwide. The glutamate/aspartate transporter SLC1A3 has been implicated in tumour metabolism and progression, but the roles of SLC1A3 in gastric cancer remain unclear. We used bioinformatics approaches to analyse the expression of SLC1A3 and its role in gastric cancer. The expression levels of SLC1A3 were examined using RT-qPCR and Western bolting. SLC1A3 overexpressing and knock-down cell lines were constructed, and the cell viability was evaluated. Glucose consumption, lactate excretion and ATP levels were determined. The roles of SLC1A3 in tumour growth were evaluated using a xenograft tumour growth model. SLC1A3 was found to be overexpressed in gastric cancer, and this overexpression was associated with poor prognosis. In vitro and in vivo assays showed that SLC1A3 affected glucose metabolism and promoted gastric cancer growth. GSEA analysis suggested that SLC1A3 was positively associated with the up-regulation of the PI3K/AKT pathway. SLC1A3 overexpression activated the PI3K/AKT pathway and up-regulated GLUT1, HK II and LDHA expression. The PI3K/AKT inhibitor LY294002 prevented SLC1A3-induced glucose metabolism and cell proliferation. Our findings indicate that SLC1A3 promotes gastric cancer progression via the PI3K/AKT signalling pathway. SLC1A3 is therefore a potential therapeutic target in gastric cancer.
