Purkinje Cells May Have Unexpected Link to Mood Disorders

Neurons in the cerebellum infected with herpesvirus may influence mental health.

Posted Aug 10, 2018

 Team Prusty at Universität Würzburg
Immunofluorescence image from the cerebellar cortex region of bipolar patients that shows proteins of human herpesviruses (red) in Purkinje neurons. Astrocytes are stained green.
Source: Team Prusty at Universität Würzburg

For the first time, researchers at the University of Würzburg have identified that active infection of Purkinje neurons in the cerebellum with a human herpesvirus (HHV-6) is associated with some psychiatric disorders. Their paper, “Active HHV-6 Infection of Cerebellar Purkinje Cells in Mood Disorders,” was recently accepted for publication in the journal Frontiers in Microbiology.

First author Bhupesh Prusty of the Institute for Virology and Immunobiology at the University of Würzburg and his Department of Microbiology team in Germany worked with colleagues in the United States at the Stanley Medical Research Institute (SMRI) to make this surprising discovery about Purkinje neurons and mood disorders.

Wikipedia Commons/ Instituto Santiago Ramón y Cajal, Madrid, Spain
Drawing of pigeon Purkinje cells (A) in the cerebellum by Santiago Ramón y Cajal, 1899.
Source: Wikipedia Commons/ Instituto Santiago Ramón y Cajal, Madrid, Spain

For centuries, most experts thought that the unique Purkinje cells of the cerebellum—which provide feedforward cerebellar output from the “little brain” to the cerebral cortex as part of our cerebro-cerebellar circuitry—only played a role in non-cognitive motor functions such as fine-tuning coordinated muscle movements in daily life and sports.

However, since the dawn of the 21st-century, the pioneering work of Jeremy Schmahmann and colleagues at Harvard Medical School’s Massachusetts General Hospital has led to a growing acceptance that the cerebellum and its Purkinje neurons are also involved in a wide range of nonmotor functions. (For more see, “Jeremy Schmahmann Untangles the Perplexity of Our Cerebellum” and “The Cerebellum Deeply Influences Our Thoughts and Emotions.”)

Wikipedia Commons/Life Sciences Databases
Cerebellum (Latin for "little brain") in red.
Source: Wikipedia Commons/Life Sciences Databases

Purkinje Cell Infection Rate Is Linked to Bipolar and Major Depressive Disorders 

Until now, the association between virus-related inflammation in the brain and mood disorders has been hard for neuroscientists to pin down. Prusty and his Germany-based group had a hunch that the human herpesviruses HHV-6A and HHV-6B might play a vital role in the genesis of certain psychiatric disorders such as bipolar disorder, schizophrenia, and major depressive disorders. To investigate this possible link, they partnered with two of the largest human brain biopsy cohorts from SMRI, which is affiliated with the Stanley Division of Developmental Neurovirology at Johns Hopkins University. 

"Inherited factors have long been known to increase the risk of developing several types of psychiatric disorders including bipolar disorder, major depressive disorder, and schizophrenia," Bhupesh Prusty said in a statement. “But there is also strong evidence that environmental factors, particularly those that lead to neuroinflammation early in life, might play an important etiologic role in the pathogenesis of these disorders as well. Viruses are such an environmental factor. Pathogens may disrupt neurodevelopment and cross-talk with the immune system at key developmental stages." 

Notably, children who are infected with a human herpesvirus at a young age usually recover and do not show any complications later in life. However, Prusty et al. speculate that these viruses can lie dormant in various organs, the salivary glands, and tissues throughout the central nervous system across a lifespan. Under certain environmental circumstances (which are not clearly understood) it appears that human herpesviruses can become active again, even after years of latency.

"We were able to find active infection of HHV-6 predominantly within Purkinje cells of human cerebellum in bipolar and major depressive disorder patients," Prusty said in a summary of this study’s significance. “The results show, for the first time, that type HHV-6 viruses are capable of infecting neurons and possibly causing cognitive disturbances leading to mood disorder.”

Interestingly, the researchers found a strong association between HHV-6A infection and reduced Purkinje cell size. This suggests that virus-mediated abnormal Purkinje cell function may be linked to bipolar disorder and major depression in some cases. An analysis of brain tissue in the cerebellum using gene expression techniques also revealed an inflammatory response to HHV-6A infection.

According to the researchers, their latest findings on a possible link between Purkinje neurons, active HHV-6, and mood disorders could disprove the widely-held belief that viruses which lie "dormant" never cause disease. “Studies like ours prove this thinking as wrong," Prusty said.

The next phase of research by Prusty and his team will be for the Würzburg researchers to pinpoint the specific molecular mechanisms driving HHV-6A mediated cellular damage to Purkinje neurons.

References

Bhupesh K. Prusty, Nitish Gulve, Sheila Govind, Gerhard R. Krueger, Julia Feichtinger, Lee Larcombe, Richard Aspinall, Dharam V. Avlashi, Carla T. Toro. "Active HHV-6 infection of cerebellar Purkinje cells in mood disorders." Frontiers in Microbiology (Provisionally accepted for publication: August 2, 2018) DOI: 10.3389/fmicb.2018.01955

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