performed the research.

Scale; LH: learned helplessness; MAO: monoamine oxidase; PCA: parachloroamphetamine; PCr: phosphocreatine; Slc6a8 -/y : male Slc6a8 knockout mice; Slc6a8 +/y : male wild type mice; Slc6a8 +/-: female mice heterozygous for Slc6a8; Slc6a8 +/+ : female wild type mice; SSRI: selective serotonin reuptake inhibitor; TPH-2: tryptophan hydroxylase-2; TST: tail-suspension test; cLH: rats bred for a congenital LH response Lack of creatine alters serotonin and affect 2 AbstractApproximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8 -/y ) and female mice heterozygous for Crt expression (Slc6a8 +/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8 -/y and Slc6a8 +/mice had more escapes and faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Elevated zero maze and tail-suspension test performance matched that of wildtype mice, however. Slc6a8 -/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while serotonin levels are unchanged. This indicates an increase in 5-HT turnover. Our results indicate that Cr plays a complex role in affective disorders and 5-HT neurotransmission, warranting further investigation. Lack of creatine alters serotonin and affect 3

The lack of cerebral creatine (Cr) causes intellectual disability and epilepsy. In addition, a significant portion of individuals with Cr transporter (Crt) deficiency (CTD), the leading cause of cerebral Cr deficiency syndromes (CCDS), are diagnosed with attention-deficit hyperactivity disorder. While the neurological effects of CTD are clear, the mechanisms that underlie these deficits are unknown. Part of this is due to the heterogenous nature of the brain and the unique metabolic demands of specific neuronal systems. Of particular interest related to Cr physiology are dopaminergic neurons, as many CCDS patients have ADHD and Cr has been implicated in dopamine-associated neurodegenerative disorders, such as Parkinson's and Huntington's diseases. The purpose of this study was to examine the effect of a loss of the Slc6a8 (Crt) gene in dopamine transporter (Slc6a3; DAT) expressing cells on locomotor activity and motor function as the mice age. Floxed Slc6a8 (Slc6a8 flox ) mice were mated to DAT IREScre expressing mice to generate DATspecific Slc6a8 knockouts (dCrt −/y ). Locomotor activity, spontaneous activity, and performance in the challenging beam test were evaluated monthly in dCrt −/y and control (Slc6a8 flox ) mice from 3 to 12 months of age. dCrt −/y mice were hyperactive compared with controls throughout testing. In addition, dCrt −/y mice showed increased rearing and hindlimb steps in the spontaneous activity test. Latency to cross the narrow bridge was increased in dCrt −/y mice while foot slips were unchanged. Taken together, these data suggest that the lack of Cr in dopaminergic neurons causes hyperactivity while sparing motor function.