FENG, Guoping, Synaptic Mechanisms in Psych Disorders, MIT, Mar 10, 2014
<p class="MsoNormal" >FENG, Guoping, Synaptic Mechanisms in Psych Disorders, MIT, Mar 10, 2014</p>
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this is at Stanford in Herrin Hall T 175 in Biology Dept at 4PM.</p>
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slide: postsynaptic complexes at Glutamatergic Synapses.; illustration;
He is at MIT in McGovern (Ann Graybiel also there)
scores of difft molecules in addition to receptors.</p>
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illustration is from review by Thomas Delorme in Nat. Med in 2013... get that.</p>
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synaptic dysfunction as a key mech. in psych disorders...</p>
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same genes may be implicated in schizo and in autism and OCD.</p>
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genes involved in 5 major psych disorders Lancet 2013.</p>
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five disorders; ADHD, ASD, BPD, Schizo, MDD, etc.</p>
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today will focus on</p>
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PSD95-SAPAP-SHANK postsynap scaffolding complex and psych disorders.</p>
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how mutations of difft genes affect the SAME circuit...</p>
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Kim and Sheng in Nat Neurosci in 2004</p>
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scaffolding proteins orchestrate the assembly of the post synap complex...</p>
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Shank links to many actin binding proteins... interacts with cytoskeleton...</p>
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his lab focuses on SAPAP (pronounced SAP app)</p>
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there are 4 SAPAPs</p>
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SAPAP3 is the only SAPAP family member highly expressed in the striatum...</p>
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implicated in many syndromes
eg in compulsive behavior...</p>
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SAPAP3 KO mouse has repetitive compulsive grooming... continuous... video clip...
they groom their skin off.</p>
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see Welch in Nature 2007. self only (not to other mice)</p>
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they groom for 4 hours a day!</p>
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so, is this repetitive compulsive behavior relevant to OCD?</p>
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1) OCD is anxiety spectrum disorder... persistent intrusive thots (obsessions)
and repetit. actions (compulsions)</p>
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OCD affects 1% of population worldwide.</p>
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dysfunc of cortico-striatal circuit is strongly implicated.</p>
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family studies OCD has genetic basis</p>
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first line is SSRI uptake inhibs.</p>
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look at SAPAP3 mutant mice... yes, they also have signif increased anxiety...</p>
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SSRI works (but I see that it also leads to decr grooming in WT mice).</p>
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is this a cortico-striatal defect in these mice?</p>
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they do find... reduced AMPAR mediated synap transmission and enhanced NMDAR med effect.</p>
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scaffolding proteins orchestrate the assembly of the postsynap complex.</p>
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he finds altered NMDAR subunits in SAPAP3 mutant mice...</p>
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perhaps this is func. immature cortico-striatal synap in sapap3 mutant mice...</p>
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with reduced AMPA current
and incr NMDA currents
and incr levels of NR2B and decr level of NR2A</p>
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so, perhaps this a striatal defect that is the cause of the OCD behavior.</p>
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first we used lentivirus-med expr of GFP-SAPAP3 in the straitum of SAPAP3 mutant mice...</p>
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lentevirus were injected at post natal day 7...</p>
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we saw RESCUE!!!! of compulsive grooming behavior with this lentevirus mediated rescue of SAPAP3.</p>
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so, how does OCD work to mediate compulsive/reptit behavior?</p>
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two main paths in Striatum either D2 or D1..SNc can either be excit or inhib...
= substantia nigra...</p>
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we made Cre-inducilbe SAPAP3 BAC transgenic mice.</p>
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so SAPAP3 is not expressed until you express Cre.</p>
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selective expression of SAPAP3 (even in adult mice!!!) rescues OCD-like behavior phenotype.</p>
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the xs grooming stops and even the hair grows back on the snout and the skin heals!!!
(after Tamox induction of Cre)</p>
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suggests that direct pathway (via D1) in striatum is most important.</p>
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see Gerfen in 2006;</p>
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note: we see this behavior in autism also;</p>
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next we tried another gene (for Shank)</p>
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there are 3 shanks but only shank3 is highly expressed in striatum...</p>
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Shank3 mutant mice also groom their skin off...</p>
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so, this seems to be CIRCUIT specific (rather than gene specific)</p>
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also have deficits of social interactions in shank3 mutant mice (he shows video clip:
they do not interact)</p>
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phobia of novel objects in shank3 mutant mice</p>
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(he tells story of Sheldon Cooper from Big Bang, not wanting to
eat french toast cuz its Monday (the wrong day))</p>
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same with the mutant mice... anything new, they dislike.</p>
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shank3 mutant mice show bioch changes in PSD...</p>
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reduces spine number and synapses...</p>
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he shows circuit again:</p>
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direct pathway (D1 pathway) goes directly to GPi/SNr (an inhibitory path) and then
inhib to thalamus.</p>
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seems to create an imbalance in activity btwn direct and indirect pathways of basal ganglia.</p>
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D2 path has decr EPSPs and incr IPSCs.</p>
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so (in above) many genes causes similar OCD behavior.
topic two*</p>
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next topic: mutations of one gene affecting different circuits:</p>
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shank3 involved in ASD</p>
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and shank3 involved in schizo.</p>
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shank3 is a huge gene with many promoters and many isoforms, etc.</p>
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R1117X mice show barbering behavior (social dominance)</p>
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dominant mouse shaves his cage mates (shaves their pates almost clean!)</p>
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InsG3680 +/+ relative to R1117 mice which show synaptic defect in dm PFC.</p>
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these are difft mutations in the same gene! (in shank3)</p>
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huge decrease in Homer (dramatic reduction)</p>
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defects are v close by and cause quite difft syndromes.</p>
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summary (of this) difft mutations of shank2 id'd in ASD and schizo have differential effects
on synaptic circuit function and bahvior.</p>
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many sources of support; large lab; many collabs.</p>
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Q1 mechs: balance btwn D1 and D2 is impt. (btwn direct and indirect pathway);</p>
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Q2 penetrance? A SAPAP3... v penetrant! (espec when mice are stressed out)
eg earlier hair loss on snout at an earlier age.
(from lights or social isolation)</p>
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Q3 (Carla S): Rescue experiment was beautiful; but would it also work
if you expressed sapap in cortex?
A: (missed this): he tried it and did not work.</p>
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</p>