Genetic Mouse Models for the Study of Serotonin, Dopamine and Glutamate Function and Behavior

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As recently reviewed by us, SERT-deficient +/- and -/- mice have gene-proportionate increases in extracellular fluid serotonin concentrations, i.e., 5- or 7-fold excesses respectively over wildtype +/+ mice. At the same time, SERT -/- mice have a marked deficit of intracellular, releasable serotonin. To investigate a rare variant in the serotonin transporter, I425V, strongly associated with obsessive-compulsive disorder and more recently, Tourettes Disorder in our own studies published over the last several years and most recently last year, a mouse model was created in C57B6 mice with this gene alteration. Preliminary results of initial investigations were reported at the ACNP meeting in 2013 (Ramamoorthy, Murphy DL, et al.) and will also be reported at the Society for Neuroscience meeting on November, 2014 Continuing advances have been made in our studies of serotonin-related toxic reactions, including the serotonin syndrome. Most commonly, this toxicity occurs as a side effect in humans treated with certain antidepressant and anti-anxiety drugs. Importantly, its milder forms contribute to reduced therapeutic efficacy or a requirement to interrupt treatment in some individuals treated with SRIs. Our earlier studies exploring this behavioral and temperature-related syndrome in SERT-deficient mice revealed a genetic vulnerability to a markedly exaggerated serotonin syndrome when these mice were exposed to the metabolic precursor of serotonin, 5-HTP, or to other serotonergic drugs such as the monoamine oxidase-inhibiting (MAO-I) antidepressant, tranylcypromine. In addition to the serotonin syndrome behavioral changes, exaggerated alterations in temperature responses were also found in SERT- and MAO-deficient mice. We have further extended these studies to include dopamine transporter (DAT) knockout mice to further explicate the unusual behavioral feature, some resembling compulsive, stereotyped behaviors related to human obsessive-compulsive disorder (OCD). We have also created both conditional EAAT3 over-expressing and conditional EAAT3 knockout mice, to investigate the functional consequences of altered expression of this important glutamate transporter. We are currently characterizing these mice at molecular, neurochemical and behavioral levels. In addition, A report about these mice was published in abstract form this year (Moya PR et al., 2013).In collaboration with Dr. Andrew Holmes at NIAAA we plan to characterize behavioral phenotypes that might arise from GAD65-Cre-mediated EAAT3 overexpression in interneurons that might shed light into the role of EAAT3 in neuropsychiatric disorders such as OCD. These findings in these mouse genetic models suggest the likelihood that humans with lower-expressing SLC6A4 SS, SLg and LgLg genotypes, or other SERT variants as well as SLC6A3 and SLC1A1 variants that may lead to 50-100% alterations in binding sites or transport function, may be at higher risk to develop neurodevelopmental disorders. Of special note, it is likely that relatively mild serotonin syndrome occurrence may contribute to early discontinuation of SRIs and other side effects during SRI treatment of neuropsychiatric patients that are strongly associated with the lower-expressing SLC6A4. Likewise variants in SLC6A3 and SLC1A1 genes have recently been found to be associated with multiple neuropsychiatric disorders such as ADHD and OCD. Our Laboratory has contributed to research on variants in these genes as noted in our other 2014 Annual Report ZIA MH000332-36 LCS. Given this transgenic mouse data and human SLC6A4, SLC6A3 and SLC1A1 polymorphism data, we have joined in multiple collaborative gene-hunting efforts to find and examine functional likely involved in neuropsychiatric disorders. Overall, the data accumulated by our Lab, as referenced below and previously in over 800 Pubmed references, support the use of different genetically modified mice as vulnerability models for humans with SERT, DAT, EAAT3 and other gene variants with regard to gene-gene and gene-environment interactions that contribute to human diseases and the pharmacologic treatment of multiple psychiatric disorders. We have published reviews of our work on these murine models in major journals (e.g., Murphy and Lesch, Nature Neuroscience, 2008). Citation numbers of other papers that have referenced our scientific reports number over 3500 as of August, 2014. The protocol number for this report is LCS 04.