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Nitrosynapsin for the Treatment of Neurological Manifestations Of Neurobiology of Disease 127 (2019) 390–397 Contents lists available at ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi NitroSynapsin for the treatment of neurological manifestations of tuberous T sclerosis complex in a rodent model Shu-ichi Okamotoa,1,2, Olga Prikhodkob,2, Juan Pina-Crespoc, Anthony Adamed, Scott R. McKerchera,e, Laurence M. Brillc,3, Nobuki Nakanishia, Chang-ki Oha,e, ⁎ Tomohiro Nakamuraa,e, Eliezer Masliahd,4, Stuart A. Liptona,d,e, a Scintillon Institute, San Diego, CA 92121, USA b Biomedical Sciences Graduate Program, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA c Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA d Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, CA 92093, USA e Neuroscience Translational Center, Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA ARTICLE INFO ABSTRACT Keywords: Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or Tuberous sclerosis TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also ex- NitroSynapsin press co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, Extrasynaptic NMDA receptor but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered sy- E/I imbalance naptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) an- Hippocampal long-term potentiation tagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/− mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that pre- ferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide bio- logical and statistically significant improvement in Tsc2+/− phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/− mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of ex- cessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC. 1. Introduction tasks. Roughly 50% of TSC patients have IQs in the normal range, while displaying neuropsychological impairment such as deficits in attention- Tuberous sclerosis complex (TSC) is an autosomal dominant dis- executive skills, memory and learning (de Vries et al., 2009; Harrison order manifested by intellectual disability, epilepsy/electro- et al., 1999; Prather and de Vries, 2004; Ridler et al., 2007). Psychiatric physiological deficits, and neurobehavioral abnormalities, often pro- comorbidities of TSC include mood, anxiety and adjustment disorders ducing features of autism spectrum disorder (ASD) (Bolton et al., 2002; (de Vries et al., 2007; Lewis et al., 2004; Muzykewicz et al., 2007; Hsieh et al., 2016; Smalley, 1998). Approximately 20–30% of in- Pulsifer et al., 2007; Raznahan et al., 2006). dividuals with TSC have very low IQs and require assistance with daily Currently, there is no cure or adequate treatment for TSC. The Abbreviations: ACSF, artificial cerebrospinal fluid; ASD, autism spectrum disorder; E/I, excitatory/inhibitory; eNMDAR, extrasynaptic NMDA-type glutamatere- ceptor; fEPSPs, field excitatory postsynaptic potentials; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; MAPKAPK2, mitogen-activated protein kinase-activated protein kinase 2; MEA, microelectrode array; TSC, Tuberous sclerosis complex;; WT, wild-type ⁎ Corresponding author at: Neuroscience Translational Center, Departments of Molecular Medicine and Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA E-mail address: [email protected] (S.A. Lipton). 1 Present address: Takeda Pharmaceutical Company, Ltd., Tokyo, Japan. 2 These authors contributed equally to the work. 3 Present address: Intertek Pharmaceutical Services, Bioanalytical and Proteomic LCMS, San Diego, CA 92121, USA. 4 Present address: National Institute on Aging/NIH, Bethesda, MD 20892, USA. https://doi.org/10.1016/j.nbd.2019.03.029 Received 31 October 2018; Received in revised form 7 March 2019; Accepted 26 March 2019 Available online 27 March 2019 0969-9961/ © 2019 Elsevier Inc. All rights reserved. S.-i. Okamoto, et al. Neurobiology of Disease 127 (2019) 390–397 disorder is caused by heterozygous mutations that inactivate one of two NitroSynapsin, by virtue of its having a second antagonist function that genes, Tsc1 or Tsc2. The TSC proteins form the TSC1/2 complex, which is not voltage dependent, i.e., S-nitrosylation of redox sites on the re- inhibits Rheb, a GTPase which activates mammalian target of rapa- ceptor that are located outside of the membrane field (Choi et al., 2000; mycin complex 1 (mTORC1). mTORC1 stimulates mRNA translation Lei et al., 1992; Lipton, 2006; Lipton et al., 1993), this shortcoming is and cell growth; excessive activation of this pathway due to the inactive avoided (Takahashi et al., 2015; Talantova et al., 2013; Wang et al., TSC1/2 complex may lead to TSC pathological features, such as ab- 2006). Of importance, NitroSynapsin is an aminoadamantane nitrate. normal signaling at synapses and aberrant subunit composition of Hence, NO-related species are donated as a nitro group from an alkyl AMPA receptors in a variety of neuronal types (Talos et al., 2008). Tsc1 nitrate that lacks the toxicity of free radical nitric oxide (NO%) since it and Tsc2 heterozygous mice have hippocampal-dependent learning and has one less electron and consequently manifests a different chemical .– − memory deficits (Ehninger et al., 2008; Goorden et al., 2007). In this reactivity (e.g., it does not react with O2 to form toxic ONOO [per- study, we used the Tsc2+/− mouse model of tuberous sclerosis because oxynitrite]) (Beckman et al., 1990; Choi et al., 2000; Dawson et al., of the higher frequency and more severe phenotype of Tsc2 mutations 1991; Lipton, 2006; Lipton, 2007; Talantova et al., 2013; Wang et al., compared to those of Tsc1 in humans although this mouse strain does 2006). not manifest epilepsy (Ehninger et al., 2008; Goorden et al., 2007; Nie One result of the mechanism of action of memantine and particu- et al., 2010; Onda et al., 1999). Tsc2+/− mice have been reported to larly of NitroSynapsin is that these antagonists selectively block ex- display learning and memory deficits due to hyperactivity of mTOR cessive, tonically-activated eNMDARs rather than the physiological signaling in addition to abnormalities in long-term potentiation (LTP) activity of synaptic (s)NMDARs, thus protecting synaptic integrity in the CA1 region of the hippocampus (Ehninger et al., 2008). Beha- (Lipton, 2006; Okamoto et al., 2009; Talantova et al., 2013; Xia et al., viorally, these mice manifest a deficit in hippocampal-dependent con- 2010). Therefore, we hypothesized that this action of memantine and text specificity, as tested by fear conditioning (Ehninger et al., 2008). NitroSynapsin might offer a rational treatment for individuals with The mechanism of pathogenesis in TSC is not entirely clear. One TSC. We thus investigated if administration of these eNMDARs an- important etiological pathway involves overstimulation of mTOR. tagonists could improve synaptic spine structure, electrophysiological Hyperactivation of mTOR in TSC results in inhibition of macro- properties, and behavioral abnormalities in TSC murine models by af- autophagy, with consequent loss of developmental synaptic spine fecting the eNMDAR/p38 mitogen-activated protein kinase (MAPK)/ pruning and behavioral abnormalities; inhibition of mTOR with rapa- MAPK activated protein kinase 2 (APK2)/TSC2 cascade. mycin can rescue these phenotypes (Tang et al., 2014). TSC-related neurological symptoms are accompanied by increased expression of N- 2. Materials and methods methyl-D-aspartate-type glutamate receptors (NMDARs), excessive glu- tamatergic (excitatory) activity, and altered synaptic spine structures 2.1. Phosphoproteomics and immunoblotting (Lozovaya et al., 2014; Tavazoie et al., 2005). Thus, we hypothesized that NMDAR antagonists might ameliorate neurological symptoms in For phosphoproteomic analysis, rat cerebrocortical cultures were TSC. exposed to NMDA after pharmacological blockade of synaptic NMDARs We initially used the drug memantine (Namenda®), which our by simultaneous exposure to bicuculine and MK-801, resulting in sti- group had previously developed, characterized, and licensed to mulation of eNMDARs as detailed previously (Hardingham et al., 2002; pharma, contributing to its FDA-approval for the treatment of mod- Okamoto et al., 2009; Talantova et al., 2013). In this method, synaptic erate-to-severe Alzheimer's disease (AD) (Lipton, 2006). We had shown NMDA channels are selectively activated and then blocked by addition that memantine is an Uncompetitive/relatively Fast Off-rate (so-called of bicuculline (to block inhibitory GABAergic transmission, thus al- ‘UFO’) antagonist of the NMDAR (Chen and Lipton, 1997; Chen et al., lowing basal activation
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