Expression of schizophrenia biomarkers in extraocular muscles from patients with strabismus: an explanation for the link between exotropia and schizophrenia?

Abstract

Recent studies have implicated exotropia as a risk factor for schizophrenia. We determined whether schizophrenia biomarkers have abnormal levels of expression in extraocular muscles from patients with strabismus and explored whether differences in gene expression between medial and lateral rectus muscles may explain the specific association of schizophrenia with exotropia but not esotropia. Samples from horizontal extraocular muscles were obtained during strabismus surgery and compared with age- and muscle type-matched normal muscles from organ donors. We used PCR arrays to identify differences in gene expression among 417 signaling molecules. We then focused on established schizophrenia-related growth factors, cytokines, and regulators of the extracellular matrix. Among 36 genes with significantly altered gene expression in dysfunctional horizontal rectus muscles, over one third were schizophrenia-related: CTGF, CXCR4, IL1B, IL10RA, MIF, MMP2, NPY1R, NRG1, NTRK2, SERPINA3, TIMP1, TIMP2, and TNF (adjusted p value ≤ 0.016667). By PCR array, expression of three of these genes was significantly different in medial rectus muscles, while eleven were significantly altered in lateral rectus muscles. Comparing baseline levels between muscle types, three schizophrenia-related genes (NPY1R, NTRK2, TIMP2) had lower levels of expression in medial rectus muscles. Despite the surprisingly large number of schizophrenia-related genes with altered gene expression levels in dysfunctional muscles, the lack of specificity for medial rectus muscles undermines a model of shared, region-specific gene expression abnormalities between exotropia and schizophrenia, but rather suggests consideration of the alternative model: that exotropia-induced aberrant early visual experiences may enable and/or contribute as a causative factor to the development of schizophrenia.

Neural crest and the patterning of vertebrate craniofacial muscles

“…Might this reflect a long‐ago lost atavistic trait? Does the unique molecular repertoire of the lateral rectus relate to the congenital myopathies that are specific to this EOM, for example, some forms of Duane's retraction syndrome (Wahl et al, ; reviewed by: Kekunnaya & Negalur, ) and, as recently hypothesized, a link with schizophrenia (Agarwal et al, )?…”

Seasonality of births in horizontal strabismus: comparison with birth seasonality in schizophrenia and other disease conditions

“…Congenital blindness (or very early loss of vision) has been reported to protect against developing schizophrenia, 64,65 while abnormal vision and/or abnormal early visual experiences (as would be frequent in children with exotropia) appears to be a significant risk factor for schizophrenia. 13 Our findings raise the possibility that exotropia is a risk factor specifically for deficit schizophrenia. The question whether people with deficit schizophrenia have exotropia more often than would otherwise be expected has not yet been tested, but should be explored.…”

“…Seasonality of births has been extensively studied for schizophrenia, [4][5][6] but one, relatively frequent condition that is a risk factor for schizophrenia, exotropic (outwards) horizontal strabismus, 13 has remained virtually unstudied for seasonal factors. Only one previous study examined seasonality of births in patient populations with horizontal strabismus: a Japanese study in the 1980s.…”

“…[4][5][6] Recent work has suggested that one type of strabismus, exotropia, is a risk factor for mental illness, 7,8 and, in particular, schizophrenia. [9][10][11][12][13] Strabismus is a deviation of eye alignment that can be vertical, but most often is horizontal. An inward deviation is called an esotropia, and an outward deviation is an exotropia.…”

Reduced surround suppression in monocular motion perception

“…We believe that in some special populations, it would be important to test the visual acuity of each eye independently and also test stereovision, because abnormalities in binocular vision caused by strabismus or other pathologies could explain the inconsistency between previous results and recent studies in depression or autism ( Norton et al, 2016 ; Schauder et al, 2017 ). For example, the rate of strabismus in autistic ( Kaplan et al, 1999 ) and schizophrenic populations ( Agarwal et al, 2017 ; Ndlovu et al, 2011 ; Toyota et al, 2004 ) is higher than in the normal population. Moreover, some studies found a higher rate of strabismus in people with epilepsy ( Jensen & Seedorff, 1976 ; Millar, 1965 ).…”