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QuickTime™ and a decompressor are needed to see this picture. GRIK2 & Bipolar Disorder Ashley Bateman QuickTime™ and a decompressor are needed to see this picture. http://www.fi.edu/learn/brain/images/mri_brain.jpg http://scienceblogs.com/seed/upload/2007/03/lab_mouse.jpg Bipolar Disorder (BPD) Manic-depressive disorder Extreme and unusual shifts in mood, energy, and ability to function Damages relationships & performance Often ends in suicide Affects > 5 million Americans, 3 in 100 adults Diagnosis QuickTime™ and a decompressor are needed to see this picture. http://beingbipolar.today.com/files/2009/04/history-of-bipolar-disorder.jpg Major Depressive Episode Persistent feelings of: Sadness Anxiety Guilt Anger Isolation Hopelessness Disturbances in sleep and appetite Fatigue and loss of interest in sexual activity Irritability Lack of motivation http://www.thelensflare.com/large/depression_22319.jpg Morbid suicidal ideation Manic Episode Distinct period of: Elevated, expansive, irritable mood state Racing thoughts Low attention span QuickTime™ and a decompressor are needed to see this picture. Easily distracted Impaired judgment Spending sprees, unusual behavior Substance abuse (esp. alcohol, stimulants) Aggressive behavior Increased sexual drive http://www.motherearthnews.com/uploadedImages/articles/issues/2008-04-01/HyperKid.jpg Famous People with BPD Hollywood: Britney Spears Jim Carey Robert Downey Jr. Linda Hamilton Vivien Leigh Ben Stiller Robin Williams Richard Dreyfuss Marilyn Monroe Tim Burton Francis Ford Coppola Musicians: Beethoven Mozart DMX Jimi Hendrix Axl Rose Sting Brian Wilson Kurt Cobain Ozzy Ozbourne Politicians: Winston Churchill Theodore Roosevelt Abraham Lincoln Napoleon Bonaparte Writers: Edgar Allen Poe Mark Twain Virginia Woolf Charles Dickens Ralph Waldo Emerson F. Scott Fitzgerald Ernest Hemingway Kurt Vonnegut Emily Dickinson T.S. Eliot Hans Christian Anderson Victor Hugo Scientists: Sir Isaac Newton Florence Nightingale Sigmund Freud Plato QuickTime™ and a decompressor are needed to see this picture. Charles Darwin! http://www.csbsny.org/images/Charles_Darwin_1881.jpg Genetic Cause of BPD? Many chromosomal regions and candidate genes appear to relate to the development of BPD Inconsistent results and scattered focus, results not replicated Epigenetics & environment? Heritability = 0.71 http://z.about.com/d/multiples/1/0/G/2/blgal176.jpg Part 1 Understand Gene & Protein GRIK2 (humans) Localized on chromosome 6 Glutamate, Receptor, Ionotropic, Kainate 2 QuickTime™ and a decompressor are needed to see this picture. Glutamate ligand Excitatory and inhibitor neurotransmission GluR6 subunit mutation impairs binding site Arrows indicate gluR6 mutation sites Neurological Correlates: The Neuroscience of Dysfunctional Behavior. Image retrieved on February 3rd, 2009. http://neurologicalcorrelates.com/wordpress/ Isoforms QuickTime™ and a decompressor are needed to see this picture. 2nd variant: additional exon at the 3’ end Frameshift & early translation termination Shorter with distinct C-terminus GRIK2 gene: 678026 bp GRIK2 coding mRNA: 4550 bp Gene function: Ontology GO Consortium Biological process Cellular component & molecular function Glutamate signaling pathway, kainate selective glutamate receptor activity Neuronal transmission events: synaptic transmission and plasticity Cell death & apoptosis http://www.nature.com/nrn/journal/v9/n6/images/nrn2379-f1.jpg GRIK2 Homologs QuickTime™ and a decompressor are needed to see this picture. GRIK2 homologues: Phylogeny QuickTime™ and a decompressor are needed to see this picture. Multiple alignment using Muscle & Tcoffee Phylogeny created using Phylogeny.fr Protein Motifs Identical result for every species’ sequence query PFAM/SMART Highly conserved nature of putative functional domains Localization in the Cell Based on what we know about receptor function, should be localized to the plasma membrane ESLpred: nucleus ??? TargetP: secretory pathway signal peptide (SP) LOCATE: secreted protein? & type I membrane protein & multipass membrane protein QuickTime™ and a decompressor are needed to see this picture. pTARGET: 100% confidence = plasma membrane http://maddgraphix.com/sci1-5l/plasma-Membrane.jpg Protein Networks QuickTime™ and a decompressor are needed to see this picture. QuickTi me™ and a decompressor are needed to see t his pict ure. http://www.bradfitzpatrick.com/store/images/products/preview/a048-cartoon-mouse-clip-art.jpg QuickTime™ and a decompressor are needed to see this picture. QuickTime™ and a decompressor are needed to see this picture. http://www.prestoncomhaltas.org.uk/assets/images/stick_person.png Key Protein Players PSD95 GRIP1 PICK1 SDCBP KLHL17 KIF17 GRIK4 PRKAA1 FOS SENP1 Interacts at postsynaptic sites, form scaffold Glutamate Receptor Interacting Protein: localized scaffold, mediation of trafficking of binding partners Protein Interacting w/ Protein Kinase C: adaptor that organizes subcellular location of membrane proteins Scaffold Protein Periplasmic Binding Protein: binds the Cterminal domains of transmembrane proteins May play a role in neuronal function Kinesin Family Member: transports NMDA vesicles Glutamate Receptor, Ionotropic, Kainate 4: excitatory neurotransmitter at synapses in CNS Protein Kinase, AMP-activated, Alpha1 subunit: cellular energy sensor conserved in all eukaryotic cells Switch Regulatory Protein, associated with apoptotic cell death Sentrin/SUMO-specific protease: covalent modification of proteins by the small ubiquitin-like protein SUMO Part 2 Phenotypic Studies Primary Literature QuickTime™ and a decompressor are needed to see this picture. Very few studies done on phenotype of GRIK2 mutant, other putative genes for BPD Rationale Recent human genetic studies: GRIK2 as potential BPD susceptibility gene Genetic linkage of BPD to chromosome 6 Genome-wide significant linkage est. by meta-analysis Specific haplotype associated with BPD Post-mortem studies QuickTime™ and a decompressor are needed to see this picture. Expression of kainate receptors in areas for mood regulation http://www.hlhl.qc.ca/documents/images/Recherche/CESH/images/cerveau.jpg Study Questions 1. Used GluR6 KO mice in behavioral tests to elucidate role of GRIK2 receptor in regards to phenotypic patterns of BPD 2. Determine potential specificity of this receptor (receptor control = GluR5) 3. Effects of lithium on GluR6 KO mice 4. Biochemical tests QuickTime™ and a decompressor are needed to see this picture. Behavioral Tests Passive-avoidance test Open-field test Monitoring home cage activity Social interaction test Elevated plus-maze test Forced swim test Resident intruder test QuickTime™ and a decompressor are needed to see this picture. Same tests done with amphetamine & lithium http://www.c2i.ntu.edu.sg/AI+CI/Humor/AI_Jokes/img/GraduateSchoolTest.gif Lithium Results QuickTime™ and a decompressor are needed to see this picture. Specific biochemical mechanism of action in mania unknown Reduced spontaneous locomotor activity Decreased aggressive behavior Decreased activity in anxiety-provoking regions Effect on elevated plus maze test Reduced immobility time in forced swim test http://pubchem.ncbi.nlm.nih.gov/ summary/summary.cgi?cid=11125 &loc=ec_rcshttp://dailymed.nlm. nih.gov/dailymed/drugInfo.cfm?i d=401 Amphetamine Results GluR6 KO mice: exhibited more spontaneous activity more responsive to amphetamine more aggressive less anxious/more risktaking behavior less immobility in forced swim test QuickTime™ and a decompressor are needed to see this picture. http://1.bp.blogspot.com/_Sa_HjZFUdJ0/RxksvRXcWsI/AAAAAAAAACM/QH55l7WHlPE/s320/Strong_Little_Mouse.jpg Future Directions Mice mutant KO of other putative BPD genes RNAi difficult because of neuronal tissue TAP tags for protein complexes of GRIK2 More (repeated) genetic linkage and mapping studies of bipolar families Role of lithium MORE RESEARCH!