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Postnatal brain development: Eye candy enzymatics

PSA is higher in the visual cortex of dark-reared mice (top) than in the cortex of littermates reared under normal light conditions (bottom). From Di Cristo et al.

NCAM is the best-known substrate for protein modification by the acidic polysaccharide PSA, although additional protein carriers (such as neuropilin-2) have now been identified. Two sialyltransferases, STX (ST8SiaII) and PST (ST8SiaIV), are known to synthesize PSA, and PSA-modified NCAM regulates embryonic stem cell migration in the brain. In the Journal of Biological Chemistry, Oltmann-Norden et al. now show how STX and PST control PSA synthesis, and Di Cristo et al. in Nature Neuroscience expand our knowledge about the functional relevance of PSA attachment.

Oltmann-Norden et al. examined the amount of PSA in the mouse brain and found that PSA levels (measured per brain) tripled from post-natal day 1 (P1) to P9, rapidly decreased until P17 and thereafter slowly reached a stable level that corresponded to 10% of the P1 level. Brains from PST^-/- mice contained similar levels of PSA as wild-type mice. However, brains that lacked STX had 40% less PSA than wild-type or PST^-/- brains at P1, and the concentration of PSA in the STX^-/- mice did not decrease with the same kinetics as wild-type or PST-deficient mice. Furthermore, the authors detected PSA-free NCAM in STX^-/- mice soon after birth, whereas unmodified NCAM appeared after P9 in PST^-/- and wild-type mice. Data from real time quantitative PCR in turn revealed that STX expression was slightly stronger than PST until P9, after which PST became more abundant. These results suggest that STX drives the dynamics of postnatal PSA synthesis in the mouse brain. However, PST also affects the PSA structure, as a lack of PST reduced the degree of PSA polymerization more strongly than an absence of STX. Thus, PST may maintain an appropriate PSA chain length in the mouse brain and support PSA expression after P9.

Di Cristo et al. analyzed the mouse visual cortex and noted a decrease in PSA levels after P14. At P28, mice reared in the dark had 44% more PSA than mice living in normal light conditions. Blocking neuronal spiking activity by Tetrodoxin injection into one eye also increased PSA content in the contralateral visual cortex. These findings suggest that PSA is downregulated by visual input during postnatal development. Premature removal of PSA by addition of the PSA-cleaving enzyme EndoN promoted the early maturation of perisomatic GABAergic innervation both in organotypic cortical culture and in the visual cortex in vivo. These findings indicate that PSA regulates the timing of the maturation of GABAergic inhibition during postnatal development. Previous studies have found that loss of visual inputs from one eye between P24 and P28 drastically shifts the responsiveness of neurons towards the functional eye, a phenomenon called ocular dominance plasticity. Di Cristo et al. found that EndoN injection between P14 and P18 caused premature onset of ocular dominance plasticity. This result is consistent with the idea that PSA removal primes the mouse brain for the initiation of ocular dominance plasticity.

Both of these studies underscore the importance of additional research about PSA function. In this regard Oltmann-Norden et al. indicate that altered STX expression has been detected in schizophrenic patients' brains, while the results of Di Cristo et al. may prompt research on the effect of PSA on adhesion and signaling factors in individual brain areas and specific neuronal circuits.

Author: Mirko von Elstermann