In AS mice the elevated association of Arc with PSD-95 is shown to interfere with the recruitment of PSD-95 to TrkB

In AS mice the elevated association of Arc with PSD-95 is shown to interfere with the recruitment of PSD-95 to TrkB. was noted 8 h following an intravenous injection of FITC-tagged CN2097, indicating that the peptide mimic is not only capable of crossing meningeal membrane barriers and selectively taken up by neurons, but also has the ability to cross the blood/brain barrier.(TIFF) pbio.1001478.s001.tiff (14M) GUID:?B480D241-5E91-4AC9-81CE-6B3860E25FE1 Figure S2: (A) Western blots showing that CN2097 alone does not stimulate Erk, Akt, or CaMKII signaling in AS brain slices, and that the control compound CN5135 does not MGF enhance BDNF signaling over levels produced by BDNF alone in WT slices. WT slices exposed to CN2097, show a 2- to 3-fold enhancement of BDNF-induced p-Akt and p-CaMKII signaling (gene. Most children with AS exhibit developmental delay, movement disorders, speech impairment, and often autistic features. The Ube3A enzyme normally regulates the degradation of the synaptic protein Arc, and in its absence the resulting elevated levels of Arc weaken synaptic contacts, making it difficult to generate long-term potentiation (LTP) and to process and store memory. In this study, we show that increased levels of Arc disrupt brain-derived neurotrophic factor (BDNF) signaling through the TrkB receptor (which is important for both the induction and maintenance of LTP). We find that the association of the postsynaptic density protein PSD-95 with TrkB is critical for intact BDNF signaling, and that the high levels of Arc in AS interfere with BDNF-induced recruitment of postsynaptic density protein-95 (PSD-95) and other effectors to TrkB. By disrupting the interaction between Arc and PSD-95 with the novel cyclic peptidomimetic compound CN2097, we were able to restore BDNF signaling and improve the induction of LTP in a mouse model of AS. We propose that the disruption of TrkB receptor signaling at synapses contributes to the cognitive dysfunction that occurs in Angelman syndrome. Introduction Angelman syndrome (AS) is a severe cognitive disorder caused by loss of expression of the maternally inherited allele of the ubiquitin ligase gene [1],[2]. As a result of imprinting, the AMD-070 HCl paternal gene is silenced, such that the maternal allele is exclusively active [3],[4]. Prominent clinical characteristics include seizures, ataxia, and mental retardation [5]. A mouse model null for maternal Ube3a [6] showed impairment in long-term potentiation (LTP) and learning [6]. Biochemically, the mice exhibited dysregulation of -calcium/calmodulin-dependent protein kinase II (CaMKII) activity [7],[8], required for certain forms of learning [9]. Ube3A ubiquitinates and degrades the immediate-early gene Arc (activity-regulated cytoskeletal-associated protein) [10], whose expression is required for LTP consolidation [11],[12] and experience-dependent plasticity [13]C[15]. Arc promotes AMPA receptor (AMPAR) internalization [16] to reduce AMPAR-mediated synaptic transmission [17], and mediates AMPAR clearance at weaker synapses AMD-070 HCl [18]. Arc has been reported to associate with postsynaptic density protein-95 (PSD-95) [19], the prototypical PDZ (PSD-95/Discs large/zona occludens-1) postsynaptic protein [20],[21], known to play a key role in the endocytosis of synaptic AMPARs [22]C[24] and to regulate AMPAR incorporation at synapses [25]C[28]. The PDZ domains of PSD-95 bind the cytoplasmic tails of select NMDA and Kainate receptor subunits [29],[30] to assemble cell-signaling scaffolds [31],[32]. To investigate the function of PSD-95, we synthesized a high affinity PSD-95 PDZ-domain peptidomimetic ligand, CN2097. AMD-070 HCl The design of CN2097 (R7-CC-YK[KTE(-Ala)]V), incorporates a lactam ring and a -alanine linker that form unique contacts outside the canonical PDZ binding pocket [33],[34]. In the present study, we sought to test if the deficit in LTP-induction in AS mice might be the result of defective brain-derived neurotrophic factor (BDNF) signaling. BDNF binding to the TrkB receptor has been shown to promote the induction and maintenance of LTP [35]C[39], and BDNF or TrkB deficient mice exhibit a marked reduction in LTP [40]C[42]. We report that PSD-95 association with TrkB is critical for intact BDNF signaling. In AS hippocampal slices, the BDNF-induced association of PSD-95 with TrkB was reduced compared to wild type (WT), resulting in attenuated PLC (CaMKII and CREB) and PI3K (Akt-mTOR) signaling, whereas MAPK (extracellular signal-regulated kinase [Erk]) signaling was intact. In AS mice the elevated association of Arc with PSD-95 is shown to interfere with the recruitment of PSD-95 to TrkB. Treatment of AS hippocampal slices with CN2097, the PSD-95 PDZ-domain peptidomimetic ligand, increases the association of PSD-95 with TrkB to restore PLC and PI3K-Akt-mTOR signaling in AS mice, and to facilitate LTP. Together, these data.

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