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Role of Gsk3ß in Behavioral Abnormalities Induced by Serotonin

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Role of Gsk3ß in Behavioral Abnormalities Induced by Serotonin Role of GSK3␤ in behavioral abnormalities induced by serotonin deficiency Jean-Martin Beaulieu*†, Xiaodong Zhang*‡, Ramona M. Rodriguiz§, Tatyana D. Sotnikova*, Michael J. Cools§, William C. Wetsel*§¶, Raul R. Gainetdinov*, and Marc G. Caron*¶ʈ** Departments of *Cell Biology, ʈMedicine, ¶Neurobiology, and §Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analyses Core Facility, Duke University Medical Center, Durham, NC 27710 Communicated by L. L. Iversen, University of Oxford, Oxford, United Kingdom, December 6, 2007 (received for review November 6, 2007) Dysregulation of brain serotonin (5-HT) neurotransmission is pharmacological stimulation of 5-HT1 receptors enhances phos- thought to underlie mental conditions as diverse as depression, phorylation of the Ser-9 residue, thus leading to inhibition of the anxiety disorders, bipolar disorder, autism, and schizophrenia. kinase (7). In contrast, 5-HT2 receptor signaling reduces GSK3␤ Despite treatment of these conditions with serotonergic drugs, the phosphorylation thus leading to kinase activation (7). Hence, a molecular mechanisms by which 5-HT is involved in the regulation general 5-HT deficiency may exert differential effects on GSK3␤ of aberrant emotional behaviors are poorly understood. Here, we activity in brain regions expressing diverse sets of 5-HT generated knockin mice expressing a mutant form of the brain receptors. 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2). This Several lines of evidence indicate that the rate-limiting en- mutant is equivalent to a rare human variant (R441H) identified in zyme for 5-HT synthesis in adult brain is tryptophan hydroxylase few individuals with unipolar major depression. Expression of 2 (Tph2) (15, 16). This enzyme catalyzes the conversion of the mutant Tph2 in mice results in markedly reduced (Ϸ80%) brain amino acid tryptophan to 5-hydroxytryptophan (5-HTP) that is 5-HT production and leads to behavioral abnormalities in tests subsequently decarboxylated to 5-HT by L-aromatic amino acid assessing 5-HT-mediated emotional states. This reduction in brain decarboxylase. Recent investigations of naturally occurring ge- 5-HT levels is accompanied by activation of glycogen synthase netic polymorphisms in humans and mice have identified func- kinase 3␤ (GSK3␤), a signaling molecule modulated by many tional mutations in Tph2 that lead to pronounced reduction in psychiatric therapeutic agents. Importantly, inactivation of GSK3␤ enzyme activity (15, 17–19). A rare R441H TPH2 variant has NEUROSCIENCE in Tph2 knockin mice, using pharmacological or genetic ap- been identified in individuals from a small cohort of elderly proaches, alleviates the aberrant behaviors produced by 5-HT patients with major unipolar depression. This mutation causes a deficiency. These findings establish a critical role of Tph2 in the reduction of Ϸ80% of enzyme activity when expressed in maintenance of brain serotonin homeostasis and identify GSK3␤ transfected PC12 cells (18). To investigate more directly the signaling as an important pathway through which brain 5-HT effects of this mutation on in vivo 5-HT synthesis, cellular deficiency induces abnormal behaviors. Targeting GSK3␤ and re- signaling, and behavior, we generated mice where the R441H lated signaling events may afford therapeutic advantages for the TPH2 mutation was engineered at the equivalent R439H amino management of certain 5-HT-related psychiatric conditions. acid residue of the mouse Tph2. Here we show that this mutation recapitulates in the mouse the neurochemical changes predicted GSK-3 ͉ mood disorders ͉ serotonin ͉ Tph2 ͉ functional polymorphism from cellular studies of the human mutant Tph2 and reveals an important role of the GSK3 signaling pathway in the behavioral erotonin (5-HT) is involved in multiple aspects of normal abnormalities associated with reduced brain 5-HT levels. brain functions ranging from the regulation of mood to the S Results control of appetite and social interactions (1–3). Several studies have suggested a contribution of abnormal 5-HT transmission in Generation of R439H Tph2 Knockin Mice. R439H Tph2 knockin mice various human psychiatric conditions and drugs acting on 5-HT were generated by using a homologous recombination strategy neurotransmission are commonly used for the management of that resulted in the insertion of the mutation in exon 11 and of major depression, anxiety disorder, obsessive-compulsive disor- a residual loxP site in the ninth intron of the gene (Fig. 1A). der, autism, and schizophrenia (1–3). Although drugs that Homozygous (HO) and heterozygous (HET) mutant mice were influence the 5-HT system can affect histone acetylation, mod- first identified using a PCR genotyping protocol detecting the ulate production of brain-derived neurotrophic factor, increase presence of the LoxP insertion in intron 9 (Fig. 1B). Subse- neural progenitor cell proliferation, and inhibit glycogen syn- quently, the presence of the mutated tph2 alleles in both HO and thase kinase 3␤ (GSK3␤) in certain brain areas (4, 5), the HET knockin mice was confirmed (Fig. 1C) by ARMS-PCR (15, mechanisms underlying the regulation of behavior by 5-HT are 20). Mice carrying the R439H mutation were viable, developed still obscure. without overt phenotype, and reproduced normally. RT-PCR There are indications that pharmacologic manipulations of confirmed the integrity of the mutated R439H Tph2 transcript 5-HT levels by different classes of drugs can affect distinct neuronal signaling mechanisms (6–9). For instance, multiple Author contributions: J.-M.B. and X.Z. contributed equally to this work; J.-M.B., X.Z., R.M.R., classes of 5-HT drugs, including selective 5-HT reuptake inhib- W.C.W., R.R.G., and M.G.C. designed research; J.-M.B., X.Z., R.M.R., T.D.S., M.J.C., and R.R.G. itors (SSRIs), tricyclic antidepressants, monoamine oxidase in- performed research; J.-M.B., X.Z., R.M.R., T.D.S., and R.R.G. analyzed data; and J.-M.B., X.Z., hibitors, and atypical antipsychotics (5, 7, 9), inhibit brain W.C.W., R.R.G., and M.G.C. wrote the paper. GSK3␤ signaling. GSK3␤ is also inhibited in vivo by lithium (6, The authors declare no conflict of interest. 10–12), which is often used in combination with antidepressants †Present address: CRULRG, Research Institute, Universite´Laval, Que´bec City, Canada. for the management of certain mood disorders (13). However, ‡Present address: Duke–National University of Singapore Graduate Medical School, whether these changes in GSK3␤ are incidental or contribute to Singapore. the regulation of 5-HT-related abnormal behaviors is unex- **To whom correspondence should be addressed. E-mail: [email protected]. plored (5). GSK3␤ is a constitutively active kinase that is This article contains supporting information online at www.pnas.org/cgi/content/full/ inhibited following the phosphorylation of the Ser-9 residue 0711496105/DC1. located in its amino-terminal domain (14). In mouse brain, © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0711496105 PNAS ͉ January 29, 2008 ͉ vol. 105 ͉ no. 4 ͉ 1333–1338 Downloaded by guest on September 25, 2021 Fig. 2. Neurochemical measurements of 5-HT synthesis rates and contents in R439H Tph2 knockin mice. (A) 5-HTP synthesis rates in striatum [ANOVA, FGenotype(2,21) ϭ 5.412, P Ͻ 0.012], frontal cortex [ANOVA, FGenotype(2,21) ϭ 11.791, P Ͻ 0.003], and hippocampus [ANOVA, FGenotype(2,21) ϭ 17.426, P Ͻ 0.001] from WT, HET and HO Tph2 mice. (B) 5-HT tissue contents in striatum [ANOVA, FGenotype(2,21) ϭ 19.236, P Ͻ 0.001], frontal cortex [ANOVA, FGenotype(2,21) ϭ 17.675, P Ͻ 0.001], and hippocampus [ANOVA, FGenotype(2,21) ϭ 15.319, P Ͻ 0.001]. (C) 5-HIAA tissue contents in striatum [ANOVA, FGenotype(2,21) ϭ 9.678, P Ͻ 0.001], frontal cortex [ANOVA, FGenotype(2,21) ϭ 6.238, P Ͻ 0.007], and hippocampus [ANOVA, FGenotype(2,21) ϭ8.112, PϽ0.002] of WT, HET and HO Tph2 mice (nϭ4–11 mice per group). Data are means Ϯ SEM. Bonferroni corrected pair-wise compar- isons: *, P Յ 0.05; ***, P Յ 0.005 from the WT control. hydroxybenzylhydrazine, provides a direct assessment of Tph2 activity in vivo (15). Synthesis rates in the striatum, frontal cortex (FC), and hippocampus were reduced by Ϸ40% and Ϸ80% in Fig. 1. Generation of mice expressing the R439H allele of Tph2.(A) Diagram HET and HO R439H Tph2 knockin mice, respectively (Fig. 2A). of the Tph2 locus and the targeting vector. The floxed PGK-NEO/HSV-TK Due to decreased synthesis, tissue contents of 5-HT were also cassette, flanked by the PGK-DT cassette and targeting arms, is illustrated. The substantially reduced in these same brain regions of HO R439H G1449A coding mutation was engineered in exon 11 of the mouse Tph2 gene. mice (Fig. 2B). However, in HET mice, a significant reduction After homologous recombination, ES cell clones carrying the mutated exon 11 in 5-HT contents was only apparent in the FC, suggesting that were selected using ARMS-PCR and transfected with a CRE recombinase homeostatic regulation of 5-HT levels may differ among various expression vector to remove the PGK-NEO/HSV-TK cassette resulting in a Tph2 mutant allele carrying a mutated exon 11 and a residual LoxP site in intron 9. brain regions. Finally, no differences between WT and HET The WT and mutant (Mut) alleles are shown; the location of PCR primers is R439H mice were evident in tissue levels of the 5-HT degrada- indicated, red arrows: LoxP primers, green arrows: ARMS-PCR external prim- tion product 5-hydroxyindoleacetic acid (5-HIAA), whereas the ers, blue or purple arrows: ARMS-PCR allele-specific primers. (B and C) PCR metabolite was reduced to almost undetectable levels in all brain genotyping of R439H Tph2 knockin mice.
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