Impact of Truncated Neuregulin-1 Type III Overexpression on Retinal and Visual Function in Mice.

Abstract

Introduction: Schizophrenia commonly involves multiple abnormalities, such as visual processing deficits. Neuregulin-1 (Nrg1) is a pleiotropic growth and differentiation factor that signals to receptor tyrosine kinases of the ErbB family, which possess an epidermal growth factor (EGF)-like domain. Abnormal expression of Nrg1 has been observed in individuals with schizophrenia, and pathological changes in the retina have also been reported in this population, involving changes to structural, neurochemical, and physiological aspects. However, the underlying mechanisms responsible for these changes are still not fully understood.

Methods: In our study, we utilized transgenic mouse lines overexpressing an HA-tagged truncated Nrg1 Type III variant (HA-Nrg1Gief) lacking the intracellular domain (ICD) using electroretinography (ERG), visual evoked potentials (VEP), immunohistochemistry, and synaptic recordings in the lateral geniculate nucleus (LGN).

Results: The current studies revealed a significant amplitude reduction in the group of scotopic a- and b-wave responses in middle-aged mice. In old-aged mice, scotopic a-wave amplitudes were similar between groups, while b-wave group responses were significantly higher in wild-type mice. Scotopic ERG latencies were similar in both groups and at both ages. Scotopic VEP amplitudes were significantly higher in wild-type mice at middle age, whereas VEP amplitudes were significantly higher in transgenic mice in the old-aged mice. Retrograde labelling of retinal ganglion cells (RGCs) demonstrated a significant reduction in the number of RGCs in HA-Nrg1GIEF mice in both age groups. Changes in retinal marker expression and retinal vascular abnormalities were also detected in transgenic mice. In middle-aged transgenic mice, recording of the LGN revealed increased GABAergic transmission compared to wild-type mice.

Discussion: These findings suggest that in this model abnormal Nrg1 signalling is associated with visual pathway abnormalities. The extent of disruption along the retinal and thalamocortical pathways may be modulated by age-related differences.

Conclusions: Our results suggest that this experimental model may be useful for studying visual pathway abnormalities relevant to deficits observed in schizophrenia. However, the behavioural correlates were not assessed in the present study. This study is limited by the absence of behavioural assessments linking visual and synaptic alterations to schizophrenia-related phenotypes. In addition, the sample sizes for some results were modest, and we did not perform sex-stratified analyses, which may restrict the generalizability of our findings. Future studies with larger cohorts and corresponding behavioural tests will be needed to clarify the translational relevance of this model.