In humans, loss of function of the CrT leads to intellectual impairment, loss of language, and autistic-like behavioral abnormalities, and no treatment is available 
. In order to model this disorder and also understand the role of Cr in the brain, we created CrT−/y
mice. The lack of Cr in many tissues of the CrT−/y
mice shows that the recombination resulted in a successful disruption of the CrT gene.
Human CrT deficient patients show no brain Cr using MRS 
. Similarly, Cr is absent in the brain of CrT−/y
mice. The results of this study suggest that the mouse brain is unable to synthesize Cr despite having the requisite mechanisms 
. In addition, CrT−/y
mice show Cr reductions in muscle, which is in contrast with case reports of two CrT deficient patients who had either the presence of Cr 
(although levels were not determined) or normal Cr levels in muscle 
. It is possible that these patients had a mutation that allowed for the expression of a CrT splice variant, and this is supported by mutation analysis of these patients that showed the mutations occurred outside of the known splice variants for the CrT 
. Additional studies in human CrT patients using MRS could provide useful information on the relationship between the mutations in the CrT and the presence of Cr in muscle. The only tissue in which Cr levels appear to be normal was in kidney, which could be due to the role of the kidney in Cr synthesis or elimination. It is likely that the reductions in serum Cr levels are due to the lack of absorption of Cr from the gut since the CrT is expressed in the small intestine 
, which is the hypothesized route of Cr absorption from the diet.
Similar to human CrT patients, CrT−/y mice show cognitive impairments across a variety of learning and memory tests. CrT−/y mice show spatial learning and memory deficits during the first two phases of the MWM. While the CrT−/y mice were slower swimmers than CrT+/y mice, swim speed does not affect path length; therefore this measure is not confounded by performance effects. CrT−/y mice showed no deficit during the shift phase of the MWM; however, this was because even the CrT+/y control mice could not learn this phase adequately, precluding the detection of differences between genotypes. Nonetheless, on probe trials during this third phase, the CrT−/y mice were impaired, therefore, even the little they were able to learn during this phase they could not remember as well as CrT+/y.
It is conceivable that sensory deficits play a role in the learning and memory deficits. For example, CrT is highly expressed in the retina 
, which could lead to visual problems in CrT−/y
mice. The improvement in the cued version of the MWM as well as the animals' readily observing and responding to objects during the NOR task (no animal failed to accumulate the 30 s observation criterion) suggests that the visual system is not disrupted in the CrT−/y
mice sufficiently to impair visually-mediated tests. In addition, the CrT−/y
mice acquired the platform's location as shown by CrT−/y
mice having an average latency of 46 s out of a 90 s trial during the acquisition phase, suggesting that distal visual cues were used by the CrT deleted mice to navigate to the platform. This suggests that neither sensorimotor nor motivational impairments contributed to the observed deficits.
During the probe trials, CrT−/y mice showed impaired reference memory compared with CrT+/y mice. In addition to the probe trials, mice were assessed for memory in the NOR and conditioned fear tests. CrT−/y mice showed reduced memory in both of these tasks. The deficits in memory across tasks combined with the learning trials in the MWM suggest that CrT−/y mice have a general cognitive impairment. In humans, the type of learning deficit has not been characterized in detail because the phenotype prevents systematic assessment (Byars, personal communication).
There appears to be a disruption of the serotonergic system in CrT−/y
mice as evidenced by increases in 5-HT in hippocampus and prefrontal cortex along with increased 5-HT turnover in the neostriatum and hippocampus. It has been shown that serotonergic drugs such as fluoxetine and paroxetine increase Cr kinase activity 
, suggesting a relationship between 5-HT and Cr. Additionally, exposure to 5-HT, the 5-HT1A
receptor agonist 8-hydroxy-N,N-dipropyl-2-aminotetralin, or fluoxetine increases the speed of anterograde mitochondrial transport in hippocampal neurons, while serotonergic antagonism slows mitochondrial transport 
. Further, there have been recent reports suggesting that 5-HT may play a role in mitochondrial activity, as 5-HT receptor agonists increase ATP and ATP synthase β levels as well as increase basal cellular respiration in kidney cells 
. It is possible that the neurons of the PFC and hippocampus increased 5-HT activity in response to a reduction in cellular energy sources. As increases in 5-HT have been shown to alter neuronal structure and behavior 
, it is possible that the 5-HT changes are involved in the behavioral effects, including anxiety. CrT−/y
mice spend more time in the periphery of the locomotor chamber with no change in central time; since central movement reflects anxiety, the data suggest that anxiety is not altered in these mice. Additional tests of anxiety will be required to address this in greater depth, including testing for a relationship between these behaviors and changes in 5-HT.
In sum, the CrT−/y mouse provides a tool for studying the relationship between Cr and 5-HT. More broadly, CrT−/y mice exhibit cognitive deficits similar to those seen in CrT deficient patients and as such provides a model with good fidelity to the human condition suitable to test potential therapies for this currently untreatable disorder.