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Schizophr Bull. 2015 Jan;41(1):123-32. doi: 10.1093/schbul/sbu032. Epub 2014 Mar 12.

Persistent infection by HSV-1 is associated with changes in functional architecture of iPSC-derived neurons and brain activation patterns underlying working memory performance.

Author information

1
Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA; These authors contributed equally to the article.
2
Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA;
3
Department of Biology, University of Bari "Aldo Moro", Bari, Italy;
4
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA;
5
Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD;
6
Department of Genetics and The Human Genome Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ;
7
Stanley Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD;
8
Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Molecular Genetics & Biochemistry, University of Pittsburgh, Pittsburgh, PA;
9
Department of Psychiatry, WPIC, University of Pittsburgh, School of Medicine, Pittsburgh PA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA vishwajitnl@upmc.edu.

Abstract

BACKGROUND:

Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.

METHODS:

Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.

RESULTS:

HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10(-4); 2-back, P = 1.39 × 10(-5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.

CONCLUSIONS:

The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.

KEYWORDS:

fMRI; herpes; herpes simplex virus type 1; induced pluripotent stem cells; memory

PMID:
24622295
PMCID:
PMC4266288
DOI:
10.1093/schbul/sbu032
[Indexed for MEDLINE]
Free PMC Article

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