title: Deletion of novel protein TMEM35 alters stress-related functions and impairs long-term memory in mice.
abstract: The mounting of appropriate emotional and neuroendocrine responses to environmental stressors critically depends on the hypothalamic-pituitary-adrenal (HPA) axis and associated limbic circuitry. Although its function is currently unknown, the highly evolutionarily conserved transmembrane protein 35 (TMEM35) is prominently expressed in HPA circuitry and limbic areas, including the hippocampus and amygdala. To investigate the possible involvement of this protein in neuroendocrine function, we generated tmem35 knockout (KO) mice to characterize the endocrine, behavioral, electrophysiological, and proteomic alterations caused by deletion of the tmem35 gene. While capable of mounting a normal corticosterone response to restraint stress, KO mice showed elevated basal corticosterone accompanied by increased anxiety-like behavior. The KO mice also displayed impairment of hippocampus-dependent fear and spatial memories. Given the intact memory acquisition but a deficit in memory retention in the KO mice, TMEM35 is likely required for long-term memory consolidation. This conclusion is further supported by a loss of long-term potentiation in the Schaffer collateral-CA1 pathway in the KO mice. To identify putative molecular pathways underlying alterations in plasticity, proteomic analysis of synaptosomal proteins revealed lower levels of postsynaptic molecules important for synaptic plasticity in the KO hippocampus, including PSD95 and N-methyl-d-aspartate receptors. Pathway analysis (Ingenuity Pathway Analysis) of differentially expressed synaptic proteins in tmem35 KO hippocampus implicated molecular networks associated with specific cellular and behavioral functions, including decreased long-term potentiation, and increased startle reactivity and locomotion. Collectively, these data suggest that TMEM35 is a novel factor required for normal activity of the HPA axis and limbic circuitry.
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Kennedy
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, Minnesota;
authors.forename: Jiva G
authors.initials: JG
authors.lastname: Dimova
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Dakoji
authors.affiliation: Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota;
authors.forename: Li-Lian
authors.initials: LL
authors.lastname: Yuan
authors.affiliation: Department of Psychology, University of Minnesota, Minneapolis, Minnesota; Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota; Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota jgewirtz@umn.edu.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Gewirtz
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota; and Center for Neurobehavioral Development, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Phu V
authors.initials: PV
authors.lastname: Tran
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal; D001923:Brain Chemistry / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D017353:Gene Deletion; D007030:Hypothalamo-Hypophyseal System; D008565:Membrane Proteins / Q000235:genetics*; D008569:Memory Disorders / Q000235:genetics* / Q000523:psychology; D057567:Memory, Long-Term; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010913:Pituitary-Adrenal System; D040901:Proteomics; D015398:Signal Transduction / Q000502:physiology; D013315:Stress, Psychological / Q000235:genetics*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C000621395:tmem35 protein, mouse; D003345:Corticosterone
keywords: HPA axis; anxiety; hippocampus; neural plasticity; proteomic