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, C) Pharmacological blockade of NMDA receptors and L-VGCCs inhibits brief PTXinduced dissociation of mGluR5-Homer in WT cultures, as assessed by co-IP. The specific inhibitors: NMDA receptor, p.5

. L-type, Voltage gated Calcium channel: nimodipine; mGluR5: MPEP; mGluR1: LY367385. n=4

, D) Pharmacological blockade of CaMKII inhibits brief PTX-induced dissociation of mGluR5-Homer in WT cultures, as assessed by co-IP. The specific inhibitors tested are: CaMKII: KN-93 and CaMKIINtide

, Co-expression of a shRNA-resistant CaMKII? (CaMKII?res) rescues PTX-induced decreases in mGluR5-Homer. n=5. All experiments are repeated in at least 3 independent cultures. In all figures, error bars represent SEM

, C) Knockdown of endogenous H1 and H2 and replacement of H2 with a myc-tagged dephosphomimetic (S117/S216AA) prevents activity-induced dissociation of mGluR5-Homer cortical neurons

, Representative dendritic spine images (left to right) of Homer3-Venus fluorescence, mGlu5-luc emission (Em) at 480, Em535 from Homer-Venus as a result of BRET from mGluR5luc, and Em535/480 ratio. Scale bar= 1 µM. Red line indicates region of quantification of BRET of spine and dendritic shaft

A. , Brief depolarization (5 min; 55mM KCl) of WT neurons transfected with wildtype Homer3-Venus reduces the mGluR5-Homer BRET in spines

. Guo, , p.23

, Author manuscript; available in PMC, Cell Rep, 2015.

B. , WT neurons expressing a dephosphomimetic Homer3(AAA)-Venus display normal spine BRET under basal (3mM KCl) conditions, but no change in BRET in response to 55mM KCl

C. Wt, neurons expressing a phosphomimetic Homer3(DDD)-Venus display reduced spine BRET under basal (3mM KCl) conditions, and no change in BRET in response to 55mM KCl

D. Fmr1, KO neurons expressing Homer3-Venus show reduced BRET in spines under basal conditions

E. , Group spine BRET values from each condition. n = 3 cultures and 8-16 spines/condition

, C) Total and phosphorylated (T286) CaMKII? levels are elevated in total lysates and PSD fractions from Fmr1 KO cortex

, Knockdown of CaMKII? (shCaMKII?) restores mGluR5-Homer interactions in cultured Fmr1 KO cortical neurons in comparison to control shRNA (shCtrl) transfected cultures. Blots of mGluR5 after co-IP with Homer, p.4

. C)-acute, Inhibition of CaMKII activity by KN93 rescues prolonged neocortical UP states in Fmr1 KO neocortical slices. Left: Representative traces of UP states from each condition

, D) Genetic reduction of CaMKII? in Fmr1 KO/CaMKII? +/? mice rescues mGluR5-Homer interaction in Fmr1 KO mice. The front cortex tissue lysates were from WT/WT, p.1

. Ko/wt, +. Wt/camkii?, +. Ko/camkii?, and . Mice, Western blots of mGluR5 after coimmunoprecipitation (IP) with Homer antibody (top)

K. O. Cross-fmr1, . Mice, and +. Camkii?, ? mice rescues audiogenic seizures. Fmr1 KO mice had an increased seizure score, the audiogenic seizure score was reduced in Fmr1 KO/ CaMKII? +/? mice (n = 35, 37, 28 and 21 mice for