The primary visual cortex (V1) is exquisitely sensitive to changes in activity during a critical period of early development. In mice, suturing the lids of one eye (monocular deprivation, MD) during this time shifts the strength of cortical responses in the binocular zone in favor of the open eye. In an effort to uncover the molecular mechanisms underlying this ocular dominance plasticity, previous DNA microarray studies were performed examining gene expression changes after MD (Tropea et al., Nature Neurosci., 2006). Interestingly, these studies identified the Janus kinase/Signal transducer and activator of transcription 1 (JAK/STAT1) signaling pathway as being significantly upregulated in V1 in response to MD. While studied mainly for its role in cell-mediated immunity, JAK/STAT1 signaling also functions in the nervous system, modifying gene expression in response to cytokines and growth factors during development, nerve injury, and disease. STAT1 is also a prime locus for modulating plastic changes during MD, as it is a point of convergence for multiple signaling pathways involved in neuronal plasticity.
  In order to confirm JAK/STAT upregulation at the protein level, we examined cortical STAT1 expression using slice immunohistochemistry and western blot analysis. We found that MD increases immunostaining for activated STAT1 in diverse cortical cell types contralateral to the deprived eye. We also observed increased STAT1 levels in cortical protein extracts after 7 days of MD, an effect that could be mimicked by 7 days systemic administration of the STAT1-specific agonist interferon-gamma (IFN). In order to understand the effects of JAK/STAT1 modulation during MD, STAT1 signaling was enhanced via daily administration of IFN, in mice with or without concurrent critical period MD. Changes in ocular dominance were measured using intrinsic signal optical imaging. Strikingly, IFN treatment during MD prevented the shift in cortical responses toward the nondeprived eye, and had no significant effect on ocular dominance in nondeprived mice. Furthermore, in addition to reducing functional plasticity, IFN treatment also minimized deprivation-induced changes in spine morphology, measured from layer 5 pyramidal cell apical dendrites located in layers 2/3. Contrary to untreated mice receiving 7 days of MD, IFN-treated mice exhibited no significant decrease in the proportion of stubby spines, nor an increase in filopodia after 7 days of MD. Altogether, these data point to a homeostatic role for JAK/STAT signaling during MD, counterbalancing the functional and structural changes that take place during sensory deprivation.

Supported by: EY015068 and EY017098 and 1F32EYO17240 (DT)