Decreased home cage movement and oromotor impairments in adult Fmr1-KO mice.

Fragile X syndrome (FXS) is a common inherited disorder that significantly impacts family and patient day-to-day living across the entire life span. The childhood and adolescent behavioral consequences of FXS are well appreciated. However, there are significantly fewer studies (except those examining psychiatric comorbidities) assessing behavioral phenotypes seen in adults with FXS. Mice engineered with a genetic lesion of fragile X mental retardation 1 (Fmr1) recapitulate important molecular and neuroanatomical characteristics of FXS, and provide a means to evaluate adult behavioral phenotypes associated with FXS. We give the first description of baseline behaviors including feeding, drinking, movement and their circadian rhythms; all observed over 16 consecutive days following extensive environmental habituation in adult Fmr1-KO mutant mice. We find no genotypic changes in mouse food ingestion, feeding patterns, metabolism or circadian patterns of movement, feeding and drinking. After habituation, Fmr1-KO mice show significantly less daily movement during their active phase (the dark cycle). However, Fmr1-KO mice have more bouts of activity during the light cycle compared with wild types. In addition, Fmr1-KO mice show significantly less daily water ingestion during the circadian dark cycle, and this reduction in water intake is accompanied by a decrease in the amount of water ingested per lick. The observed water ingestion and circadian phenotypes noted in Fmr1-KO mice recapitulate known clinical aspects previously described in FXS. The finding of decreased movement in Fmr1-KO mice is novel, and suggests a dissociation between baseline and novelty-evoked activity for Fmr1-KO mice.

Microarray analysis of homocysteine-responsive genes in cardiac neural crest cells in vitro.

The amino acid homocysteine increases in the serum when there is insufficient folic acid or vitamin B(12), or with certain mutations in enzymes important in methionine metabolism. Elevated homocysteine is related to increased risk for cardiovascular and other diseases in adults and elevated maternal homocysteine increases the risk for certain congenital defects, especially those that result from abnormal development of the neural crest and neural tube. Experiments with the avian embryo model have shown that elevated homocysteine perturbs neural crest/neural tube migration in vitro and in vivo. Whereas there have been numerous studies of homocysteine-induced changes in gene expression in adult cells, there is no previous report of a homocysteine-responsive transcriptome in the embryonic neural crest. We treated neural crest cells in vitro with exogenous homocysteine in a protocol that induces significant changes in neural crest cell migration. We used microarray analysis and expression profiling to identify 65 transcripts of genes of known function that were altered by homocysteine. The largest set of effected genes (19) included those with a role in cell migration and adhesion. Other major groups were genes involved in metabolism (13); DNA/RNA interaction (11); cell proliferation/apoptosis (10); and transporter/receptor (6). Although the genes identified in this experiment were consistent with prior observations of the effect of homocysteine upon neural crest cell function, none had been identified previously as response to homocysteine in adult cells.