title: PDE11A negatively regulates lithium responsivity.
abstract: Lithium responsivity in patients with bipolar disorder has been genetically associated with Phosphodiesterase 11A (PDE11A), and lithium decreases PDE11A mRNA in induced pluripotent stem cell-derived hippocampal neurons originating from lithium-responsive patients. PDE11 is an enzyme uniquely enriched in the hippocampus that breaks down cyclic AMP and cyclic GMP. Here we determined whether decreasing PDE11A expression is sufficient to increase lithium responsivity in mice. In dorsal hippocampus and ventral hippocampus (VHIPP), lithium-responsive C57BL/6J and 129S6/SvEvTac mice show decreased PDE11A4 protein expression relative to lithium-unresponsive BALB/cJ mice. In VHIPP, C57BL/6J mice also show differences in PDE11A4 compartmentalization relative to BALB/cJ mice. In contrast, neither PDE2A nor PDE10A expression differ among the strains. The compartment-specific differences in PDE11A4 protein expression are explained by a coding single-nucleotide polymorphism (SNP) at amino acid 499, which falls within the GAF-B homodimerization domain. Relative to the BALB/cJ 499T, the C57BL/6J 499A decreases PDE11A4 homodimerization, which removes PDE11A4 from the membrane. Consistent with the observation that lower PDE11A4 expression correlates with better lithium responsiveness, we found that Pde11a knockout mice (KO) given 0.4% lithium chow for 3+ weeks exhibit greater lithium responsivity relative to wild-type (WT) littermates in tail suspension, an antidepressant-predictive assay, and amphetamine hyperlocomotion, an anti-manic predictive assay. Reduced PDE11A4 expression may represent a lithium-sensitive pathophysiology, because both C57BL/6J and Pde11a KO mice show increased expression of the pro-inflammatory cytokine interleukin-6 (IL-6) relative to BALB/cJ and PDE11A WT mice, respectively. Our finding that PDE11A4 negatively regulates lithium responsivity in mice suggests that the PDE11A SNPs identified in patients may be functionally relevant.
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: G
authors.initials: G
authors.lastname: Pathak
authors.affiliation: Pfizer, Andover, MA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Agostino
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Bishara
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Capell
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Fisher
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Hegde
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Pilarzyk
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sabin
authors.affiliation: Pfizer, Groton, CT, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tuczkewycz
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Kelly
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D055503:Protein Multimerization; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013045:Species Specificity
chemical_list: D011619:Psychotropic Drugs; D012333:RNA, Messenger; D016651:Lithium Carbonate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C520793:Pde11a protein, mouse