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Genetic deletion of glycine transporter 1 (GlyT1) in forebrain neurons gives rise to multiple-procognitive phenotypes, presumably due to enhanced N-methyl-d-aspartate receptor (NMDAR) functions. However, concerns over possible harmful excitotoxic effects under lifelong elevation of synaptic glycine have been raised. Such effects might accelerate the aging process, weakening or even reversing the procognitive phenotypes identified in adulthood. Here, we examined if one of the most robust phenotypes in the mutant mouse line (CamKIIαCre;GlyT1tm1.2fl/fI), namely, enhanced aversive Pavlovian conditioning, might be modified by age. Comparison between 3-month-old (adult) and 22-month-old (aged) mutants confirmed the presence of this phenotype at both ages. However, the temporal expression of the Pavlovian phenotype was modified in senescence; while adult mutants showed a pronounced within-session extinction, aged mutants did not. Expression of NR2B subunits of NMDAR and neural proliferation were examined in the same animals by immunohistochemistry. These were reduced in the aged mice as expected, but not exacerbated by the mutation. Thus, our results do not substantiate the concerns of neurotoxic effects through lifelong GlyT1 disruption in forebrain neurons, but provide evidence for a modification of phenotypic expression as a function of age. The latter points to the need to further investigate other procognitive phenotypes identified at adulthood in this mutant line. In addition, we revealed here for the first time a clear increase in the number of immature neurons in the hippocampus of the mutants, although the behavioral significance of this phenotype remains to be determined.

Impacts of forebrain neuronal glycine transporter 1 disruption in the senescent brain: Evidence for age-dependent phenotypes in Pavlovian learning.