SynGAP is expressed in the murine suprachiasmatic nucleus and regulates circadian‐gated locomotor activity and light‐entrainment capacity

Nov 11, 2020The European journal of neuroscience

SynGAP protein in the mouse brain’s circadian center affects daily movement patterns and response to light

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Abstract

SynGAP is broadly expressed in the suprachiasmatic nucleus (SCN) and peaks during the circadian night.

SynGAP expression is regulated over the circadian cycle, indicating its role in the timing of biological processes.
The daily oscillation in SynGAP expression is driven by the circadian timing mechanism, as shown by its absence in clock arrhythmic BMAL1 null mice.
SynGAP phosphorylation at serine 1138 is influenced by the time of day and photic input, suggesting its functional modulation is time-dependent.
Circadian phenotypic analysis of Syngap1 heterozygous mice shows increased locomotor activity and heightened sensitivity to light-evoked clock entrainment.
Elevated light-evoked MAPK activity in these mice aligns with SynGAP's role as a negative regulator of MAPK signaling.

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The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian clock. The phasing of the SCN oscillator is locked to the daily solar cycle, and an intracellular signaling cassette from the small GTPase Ras to the p44/42 mitogen-activated protein kinase (ERK/MAPK) pathway is central to this entrainment process. Here, we analyzed the expression and function of SynGAP-a GTPase-activating protein that serves as a negative regulator of Ras signaling-within the murine SCN. Using a combination of immunohistochemical and Western blotting approaches, we show that SynGAP is broadly expressed throughout the SCN. In addition, temporal profiling assays revealed that SynGAP expression is regulated over the circadian cycle, with peak expression occurring during the circadian night. Further, time-of-day-gated expression of SynGAP was not observed in clock arrhythmic BMAL1 null mice, indicating that the daily oscillation in SynGAP is driven by the inherent circadian timing mechanism. We also show that SynGAP phosphorylation at serine 1138-an event that has been found to modulate its functional efficacy-is regulated by clock time and is responsive to photic input. Finally, circadian phenotypic analysis of Syngap1 heterozygous mice revealed enhanced locomotor activity, increased sensitivity to light-evoked clock entrainment, and elevated levels of light-evoked MAPK activity, which is consistent with the role of SynGAP as a negative regulator of MAPK signaling. These findings reveal that SynGAP functions as a modulator of SCN clock entrainment, an effect that may contribute to sleep and circadian abnormalities observed in patients with SYNGAP1 gene mutations.

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SynGAP is expressed in the murine suprachiasmatic nucleus and regulates circadian‐gated locomotor activity and light‐entrainment capacity

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