Ataxic movement, the common major symptom of
spinocerebellar atrophy, has been considered to involve impaired glutamatergic excitatory neurotransmission in the cerebellum. Considering the therapeutic importance of
ataxia control, we assessed the effectiveness of increasing the extracellular concentration of
glycine by administering it exogenously or via blockade of
glycine transporter 1, using its selective inhibitors
sarcosine and N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl]
sarcosine (NFPS), for amelioration of
motor ataxia in a mouse model of
spinocerebellar atrophy developing after neonatal treatment with
cytosine beta-D-arabinofuranoside. Intracerebroventricular (i.c.v.) injection of
sarcosine (3, 10, and 30 microg) and NFPS (0.01 and 0.03 microg) reduced the number of falls without affecting spontaneous motor activity, and therefore the falling index [(number of falls / spontaneous motor activity) x 100], and dose-dependently ameliorated ataxic movements. Similar effects were observed upon i.c.v. injection of D-
serine (1 and 10 microg), an agonist of the
glycine-recognition site of the
N-methyl-D-aspartate (
NMDA) receptor. However, exogenously injected
glycine (1, 3, and 10 microg, i.c.v.) only weakly ameliorated the ataxic movements at 3 microg. These results suggest the therapeutic relevance of GlyT1 inhibitors for amelioration of
motor ataxia in
spinocerebellar atrophy by increasing the endogenous concentration of
glycine near the
glycine-recognition site of the
NMDA receptor.