Figure 6.

TARPγ-8-mediated GluA1 expression in the PSD fraction is associated with behavioral resilience to chronic stress

(A) Expression of the Cacng8 gene (encoding TARPγ-8) by RNA FISH (RNAscope) in a coronal section of the mouse brain. vCA1, ventral part of CA1 in the hippocampus. Scale bar, 50 μm.

(B and C) Immunoblot estimation of phosphorylated TARPγ-8 (pTARPγ-8) and total TARPγ-8 levels in the vCA1 of BALB and B6 mice exposed to subchronic and mild social defeat stress (smSDS) or no stress (NS). n = 8–10 mice per group.

(D) Linear correlation between pTARPγ-8 levels and postsynaptic membrane (PSD) GluA1 levels in the vCA1 of BALB and B6 mice.

(E) Linear correlation between pTARPγ-8 levels in the vCA1 and social interaction in BALB and B6 mice.

(F) Schematic representation of the AAV vectors engineered to overexpress a constitutively active form of TARPγ-8 (AAV-TARPγ-8^D/D-T2A-mCherry) or a control construct (AAV-mCherry).

(G) Experimental paradigm for behavioral testing. BALB mice were injected with AAV-TARPγ-8^D/D-T2A-mCherry or AAV-mCherry and subjected to 5-day smSDS exposure. SIT, social interaction test; SPT, sucrose preference test.

(H) Coronal view of mCherry signals in the vCA1 of BALB mice injected with AAV-TARPγ-8^D/D-T2A-mCherry. Scale bar, 100 μm.

(I and J) No change in synaptosomal GluA1 levels was observed between mice injected with AAV-TARPγ-8^D/D-T2A-mCherry and AAV-mCherry (I). BALB mice overexpressing TARPγ-8^D/D show increased PSD GluA1 levels in the PSD fraction under stress condition (J). n = 8 mice per group.

(K and L) TARPγ-8^D/D overexpression leads to a significant increase of time in the interaction zone in the SIT (K) and sucrose preference in the SPT (L). n = 14–16 mice per group.

(M) Overexpression of TARPγ-8^D/D increases Fos levels in the vCA1 of BALB mice following smSDS exposure. n = 6 mice per group.

(N) Experimental paradigm for stress exposure and behavioral testing.

(O) SIT occupancy heat maps during target session obtained by averaging the location of testing animals in each group.

(P) GluA1^CT overexpression prevents the increase in social interaction time induced by the activation of TARPγ-8 under the smSDS condition. n = 12 mice per group.

(Q) Experimental paradigm for stress exposure, drug treatment, and behavioral testing.

(R) B6 mice given vehicle control showed normal social interaction following smSDS exposure, but intra-vCA1 JNJ55511118 injection decreased time in the interaction zone.

One-way ANOVA followed by a Tukey's post hoc test (in P), two-way ANOVA followed by a Tukey's post hoc test (in C and R), two-tailed Student's t-test (in I-M), and Pearson's correlation (in D and E) were used for statistical analyses. ∗p < 0.05. Bar graphs show mean ± SEM.

See also Figure S6. Complete statistical summaries are provided in Table S2.