Loss of PEA-15 Alters ERK/MAPK Signaling and Circadian Function in the Suprachiasmatic Nucleus

Circadian rhythms are a fundamental biological process that coordinates physiological functions, behavior, and metabolism with an approximately 24-hour periodicity. At the center of the mammalian circadian timing system is the suprachiasmatic nucleus (SCN) of the hypothalamus, which generates robust, clock-gated neuronal output that establishes the temporal organization of cellular and physiological processes throughout the body. Our previous work demonstrated that the scaffold protein PEA-15 (phosphoprotein enriched in astrocytes 15) is highly expressed in the SCN and dynamically interacts with ERK, a key effector kinase of the MAPK pathway, to regulate its subcellular localization. Given the important role of ERK/MAPK signaling in circadian timing and photic entrainment, we extended this work using PEA-15 knockout (PEA-15−/−) mice to determine how loss of PEA-15 affects circadian timing, entrainment, and ERK signaling within the SCN. At the cellular level, both clock-gated and light-evoked ERK activation were significantly reduced in PEA-15−/− mice compared with wild-type controls. Under constant darkness, PEA-15−/− mice exhibited a significantly shorter free-running period and reduced locomotor activity relative to wild-type animals. Assessment of circadian entrainment using jet-lag resetting and Aschoff type I light-pulse paradigms revealed a blunted phase-delay response to light and an accelerated rate of entrainment to a phase-advancing light stimulus. Thus, loss of PEA-15 alters multiple properties of the SCN clock, including its intrinsic period and its responsiveness to photic input, with effects that depend on the direction of phase resetting. Collectively, these findings identify PEA-15 as an important regulator of SCN circadian function and implicate ERK/MAPK signaling as one mechanism through which PEA-15 modulates clock timing and photic entrainment.