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GRIK2 & Bipolar Disorder
Ashley Bateman
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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
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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
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Morbid suicidal ideation
Manic Episode
Distinct period of:
Elevated, expansive, irritable mood state
Racing thoughts
Low attention span
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Easily distracted
Impaired judgment
Spending sprees, unusual behavior
Substance abuse (esp. alcohol, stimulants)
Aggressive behavior
Increased sexual drive
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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
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Charles Darwin!
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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
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Part 1
Understand Gene &
Protein
GRIK2 (humans)
Localized on chromosome 6
Glutamate, Receptor,
Ionotropic, Kainate 2
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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
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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
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GRIK2 homologues:
Phylogeny
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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
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pTARGET: 100% confidence =
plasma membrane
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Protein Networks
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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
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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
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Expression of kainate receptors in
areas for mood regulation
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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
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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
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Same tests done with amphetamine & lithium
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Lithium Results
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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
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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!