Skip to main content

Verified by Psychology Today

Study Uncovers Complex Gene Expression in Bipolar Disorder

Genes for synaptic signaling and inflammation may be linked to bipolar disorder.

Key points

  • Decreased expression patterns in two sets of genes in key areas of the brain appear to be involved in the pathology of bipolar disorder.
  • One set of genes is primarily related to synaptic transmission/plasticity, and the other is primarily related to immune/inflammatory functions.
  • Decreased expression in microglial cells may directly impact non-canonical microglial functions, with secondary immune/inflammatory effects.
GDJ/Pixabay.
Source: GDJ/Pixabay.

Researchers from Johns Hopkins University reported yesterday in Nature Neuroscience that they have identified two sets of genes whose decreased expression patterns in key areas of the brain appear to be involved in the pathology of bipolar disorder. One of these sets of genes is primarily related to synaptic transmission and plasticity, while the other set is primarily related to immune and inflammatory functions. Intriguingly, their findings further suggest that changes in immune and inflammatory function may be a secondary or downstream effect, with alterations in synaptic signaling and plasticity at the core of the genetic and molecular underpinnings of bipolar disorder.

Although previous studies have identified specific genetic variants that seem to contribute to bipolar disorder heritability, these variants only account for a small proportion of the genetic contribution to BD. Furthermore, these variants are enriched in regulatory regions of the genome, which suggests a role for transcriptional mechanisms in their etiology. The researchers, therefore, examined RNA sequencing data in samples from one of the largest single post-mortem brain sample collections for bipolar disorder and neurotypical subjects. Because gene expression is differentially regulated in different brain regions, the researchers focused on samples from areas of the brain thought to be most relevant to the pathology of bipolar disorder: the subgenual anterior cingulate cortex (sACC) and the amygdala.

As described above, two groups of genes were found to be downregulated in brain samples from patients with bipolar disorder. One group of genes primarily encodes proteins that are primarily related to synaptic transmission and plasticity, including SNC2A (encoding a voltage gated sodium channel subunit), and GRIN2A (encoding an NMDA-type glutamate receptor subunit). A variant of SCN2A has been previously associated with reduced risk for bipolar disorder, and dysregulation of NMDA-mediated glutamatergic activity has been suggested as a contributing factor in bipolar disorder.

The second group of genes is primarily specific to a special type of brain support cells: microglia. Microglia have traditionally been thought to be involved in immune activation and inflammatory responses, and previous studies have reported activated microglial cells and an elevation of both peripheral and central markers of inflammation in bipolar disorder. Although the present findings showed a seemingly contradictory decrease in expression for this group of genes, it is important to note that microglia are not solely involved in immune activation and inflammatory responses. The role of microglia in supporting synaptic function and neuronal circuit activity has become clearer in recent years. Downregulation of microglia in bipolar disorder may therefore produce a primary change in neuronal activity and synaptic function instead of directly altering classic inflammatory processes.

lircoglu/Pixabay.
Source: lircoglu/Pixabay.

Further evidence that changes in immune activation and inflammatory responses may represent a downstream effect come from the fact that over a quarter of the differentially expressed genes in the microglia-specific group of genes converged on the Nuclear factor kappa B (NF-κB) pathway. NF-kB regulates multiple aspects of immune functions and mediates inflammatory responses, but it also has effects on synaptic plasticity that differentially impact different types of cells and may play a role in complex cognitive behaviors.

While much additional work is needed to tease out the complex interplay of genetics, protein expression, behavior, and environment that contribute to the etiology of bipolar disorder and its symptoms, these findings point to a convergence of evidence supporting the idea that synaptic signaling and plasticity are core genetic and molecular underpinnings of bipolar disorder.

References

Zandi, P.P., Jaffe, A.E., Goes, F.S. et al. (2022). Amygdala and anterior cingulate transcriptomes from individuals with bipolar disorder reveal downregulated neuroimmune and synaptic pathways. Nature Neuroscience, 25:381–389. https://doi.org/10.1038/s41593-022-01024-6.

Sanders, S. J. et al. (2018). Progress in understanding and treating SCN2A-mediated disorders. Trends in Neuroscience, 41:442–456. https://doi.org/10.1016/j.tins.2018.03.011.

de Sousa, R. T. et al. (2017). Genetic studies on the tripartite glutamate synapse in the pathophysiology and therapeutics of mood disorders. Neuropsychopharmacology, 42:787–800. https://doi.org/10.1038/npp.2016.149.

Pinto, J. V., Passos, I. C., Librenza-Garcia, D., et al. (2018). Neuron-glia interaction as a possible pathophysiological mechanism of bipolar disorder. Current Neuropharmacology, 16(5):519–532. https://doi.org/10.2174/1570159X15666170828170921.

advertisement