Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways

Abstract

Recent genetic studies have identified variants associated with bipolar disorder (BD), but it remains unclear how brain gene expression is altered in BD, and how genetic risk for BD may contribute to these alterations. Here, we obtained transcriptomes from subgenual anterior cingulate cortex and amygdala samples from post-mortem brains of individuals with BD and neurotypical controls, including 511 total samples from 295 unique donors. We examined differential gene expression between cases and controls, and the transcriptional effects of BD-associated genetic variants. We found two co-expressed modules that were associated with transcriptional changes in BD: one enriched for immune and inflammatory genes and the other with genes related to the post-synaptic membrane. Over 50% of BD genome-wide significant loci contained significant expression quantitative trait loci (eQTLs), and these data converged on several individual genes, including SCN2A and GRIN2A . Thus, these data implicate specific genes and pathways that may contribute to the pathology of bipolar disorder.

Low-Dose Aspirin Augments the Anti-Inflammatory Effects of Low-Dose Lithium in Lipopolysaccharide-Treated Rats

“…Similarly, several studies have demonstrated that aspirin attenuates NF-κB elicitation [ 99 , 112 ]. These findings corroborate the accumulating data attesting to altered NF-κB activity/levels in bipolar patients [ 18 , 89 , 113 , 114 ]. In preliminary rat experiments in our lab [Uzzan, Shvartsur and Azab–personal communication] exploring whether chronic low-dose Li or low-dose aspirin, as compared with their combination, influence NF-κB activity, FC, HT and HC nuclear p65 levels were measured.…”

Montelukast induces beneficial behavioral outcomes and reduces inflammation in male and female rats

“…As mentioned, a large body of data suggested that inflammation contributes to the pathophysiology of mental disorders (15,22,(125)(126)(127)(128)(129)(130)(131)(132). For example, several research papers reported increased IL-6 levels in patients with major depression (129, 130, 133), bipolar disorder (129, 131) and schizophrenia (129, 130).…”

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

“…The copyright holder for this preprint this version posted September 22, 2022. ; https://doi.org/10.1101/2022.09.21.508852 doi: bioRxiv preprint Synapse dysfunction has long been considered as a mechanism underlying SCZ and BP pathophysiology, and is implicated by human genetics and gene expression studies (Jaffe et al, 2018;Mullins et al, 2021;Singh et al, 2022;Trubetskoy et al, 2022;Zandi et al, 2022). We observed reductions in a variety of canonical PSD proteins in SCZ and BP synapses, including glutamate receptors (AMPA, NMDA, and Kainate receptors), glutamatergic signaling pathway molecules (e.g., PLCB1, APP), and postsynaptic scaffolding proteins (e.g., HOMER1 and SHANK3), which supports the large body of evidence implicating glutamatergic receptor signaling impairment as a key pathomechanism in SCZ and BP.…”

“…The copyright holder for this preprint this version posted September 22, 2022. ; https://doi.org/10.1101/2022.09.21.508852 doi: bioRxiv preprint associated with synaptic function (Mullins et al, 2021). Transcriptomic analyses from postmortem brains have also implicated synaptic pathways in pathophysiology of SCZ and BP (Jaffe et al, 2018;Zandi et al, 2022).…”

“…Recent GWAS studies have shown that BP risk variants are also enriched in genes associated with synaptic function (Mullins et al, 2021). Transcriptomic analyses from post- mortem brains have also implicated synaptic pathways in pathophysiology of SCZ and BP (Jaffe et al, 2018; Zandi et al, 2022).…”