Archival ReportCircuit-Selective Striatal Synaptic Dysfunction in the Sapap3 Knockout Mouse Model of Obsessive-Compulsive Disorder
Section snippets
Brain Slice Preparation
Animal procedures were performed according to protocol approved by the Institutional Animal Care and Use Committee of Duke University. Generation of Sapap3 KO, Drd1a-tdTomato(tg/+) transgenic and DRD2-EGFP(tg/+) transgenic mice has been previously described 7, 19, 20. From littermate pairs of postnatal day (P)21 to P25 Sapap3 wild-type (WT) and KO mice hemizygous for Drd1a-tdTomato and/or DRD2-EGFP transgenes, acute coronal or parahorizontal brain slices (300 μm thickness) were obtained as
In Striatopallidal MSNs, Circuit-Selective Analysis Is Necessary to Reveal Defect in Quantal Synaptic Events
Circuit-selective studies to examine thalamostriatal transmission were prompted by finding that SP MSNs had discordant effects of Sapap3 deletion on miniature and evoked EPSCs. In prior studies, we demonstrated that Sapap3 deletion reduced AMPAR-mediated evoked EPSCs in both SN and SP MSNs (6). In SN MSNs, this was accompanied by a significant reduction in the frequency of mEPSC events (6). However, in SP MSNs, we show here that mEPSCs are unaffected by Sapap3 deletion. No significant
Discussion
In the present study, we show for the first time that the activity of excitatory synapses onto striatal MSNs is circuit-selectively altered in the Sapap3 KO mouse model of obsessive-compulsive disorder. In explaining the basis for this functional divergence, we identify a novel difference in the postsynaptic molecular composition of corticostriatal and thalamostriatal synapses—SAPAP4 being present at thalamostriatal, but not corticostriatal, synapses. These observations advance both our
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