Intrinsic Role of Polysialylated Neural Cell Adhesion Molecule in Photic Phase Resetting of the Mammalian Circadian Clock

Abstract

The suprachiasmatic nuclei (SCN), the location of the mammalian circadian clock, are one of the few adult brain regions that express the highly polysialylated form of neural cell adhesion molecule (PSA-NCAM). A role for the polysialic acid (PSA) component of PSA-NCAM, which is known to promote tissue plasticity, has been reported for photic entrainment of circadian rhythmicity in vivo. The in vivo results, however, do not discriminate between PSA acting upstream or downstream of the glutamatergic synapses that convey photic information to the SCN. To address this key issue, we exploited an in vitro rat brain slice preparation that retains robust circadian function. As in the intact SCN, PSA levels in the isolated SCN are rhythmic, with higher levels during the early subjective day and lower levels during subjective night. Importantly, bath application of glutamate to SCN slices rapidly and transiently increases PSA levels during both the subjective day and night. Pretreating the slices with endoneuraminidase, which selectively removes PSA from NCAM and thereby prevents this increase, abolishes glutamate- and optic chiasm stimulation-induced phase delays of the SCN circadian neuronal activity rhythm. These results support the hypothesis that PSA expression in the SCN is controlled by both the circadian clock and photic input to the clock and that expression of PSA in the SCN is critical for photic-like phase shifts of the clock. Together, these results establish that such actions of PSA are manifested downstream from presynaptic retinohypothalamic terminals and therefore are intrinsic to the SCN itself.

Molecular Clock Regulates Daily α1–2-Fucosylation of the Neural Cell Adhesion Molecule (NCAM) within Mouse Secondary Olfactory Neurons

“…On the other hand, Datura stramonium agglutinin that specifically reacts with Nacetylglucosamine ␤1-6 mannose (GlcNAc␤1-6Man), reacted intensely at ZT2 (supplemental Table S1), suggesting that GlcNAc␤1-6Man glycan fluctuates in an opposing manner to ␣1-2Fuc glycan. Although previous studies have shown that polysialic acid binding to NCAM has diurnal variation in the suprachiasmatic nucleus (23,24), the signal intensity of 13 lectins in the OB that had high affinity for sialic acid was identical between day and night.…”

NCAM1 Polysialylation

“…In support of this model, copper has been shown to cause a delay in circadian neural activity rhythms (Yamada and Prosser, 2014). Addition of glutamate to a slice preparation of the SCN increases polySia-NCAM1 levels causing phase delays (Prosser et al, 2003). Pretreatment of this slice preparation of the SCN with endosialidase abolishes these phase delays (Prosser et al, 2003).…”

“…Addition of glutamate to a slice preparation of the SCN increases polySia-NCAM1 levels causing phase delays (Prosser et al, 2003). Pretreatment of this slice preparation of the SCN with endosialidase abolishes these phase delays (Prosser et al, 2003). Thus, an intricate interplay between glutamate release, the circadian control of polySia-NCAM1 and PrP C levels, as well as their ability to modulate NMDA-mediated glutamate signaling might influence the circadian phase.…”

Polysialylated Neural Cell Adhesion Molecule Promotes Remodeling and Formation of Hippocampal Synapses

“…Reports indicate that an unusual carbohydrate ␣2,8-linked polysialic acid (PSA), which appears to be exclusively associated with NCAM, is required for correct axonal branching and fasciculation in the peripheral nervous system (Rutishauser and Landmesser, 1996), lamination, and synaptogenesis of mossy fibers (Cremer et al, 1997;Seki and Rutishauser, 1998), structural plasticity in the hypothalamic-pituitary system (Theodosis et al, 1999), migration of neural precursor cells to the olfactory bulb (Hu et al, 1996;Chazal et al, 2000), synaptic plasticity in the CA1 region of the hippocampus (Becker et al, 1996;Muller et al, 1996;Eckhardt et al, 2000), spatial learning (Cremer et al, 1994;Becker et al, 1996), and circadian rhythm (Shen et al, 1997;Prosser et al, 2003). Here, we used heterogenotypic cultures containing wild-type and NCAM-deficient neurons to study the mechanisms underlying NCAM-driven preferential synapse formation.…”