Silent Synapse Activation in Epilepsy

Journal of Neurology & Stroke

Summary Review Article Epilepsy is a life-threatening chronic disease in a state of neuronal over electric activity. The precise nature of the seizure Volume 5 Issue 2 - 2016 recurrence has not been clearly. Synapses can be divided structural specializations for neurotransmission that do not produceinto silent a andphysiological functional response synapse.Silent in the synapses,receiving definedcell, may as Department of Neurology, Chongqing Medical University, China

such as long-term potentiation *Corresponding author: Zhi-Qin Xi, Department of (LTD)occur frequentlyof glutamatergic in neural synapses, circuits. areModels believed of synaptic to underlie plasticity, the seizure occurrence. Silent synapses(LTP) and containing long-term only depression receptors are transformed within minutes into activated synapses Neurology, The First Affiliated Hospital, Chongqing Medical NMDA E-mail:University, 1 You Yi Road, Chongqing 400016, China, Tel: 86- 23-89012009; Fax: 86-23-68811487; Received: June 15, 2016 | Published: November 10, 2016 postsynaptically AMPA receptor insertion and presynaptic monophosphate)transmitter releasing signal (BDNF-Cdc42 pathway. All (brain previous derived mentioned neurotrophic genes andfactor-) proteins signaling, were abnormal Calcium in influx, epilepsy cAMP(Cyclic patients and Adenosine animal better understanding on the mechanisms of silent synapses in The available silent synapses can often be rapidly activated, and epilepsy.models. Future experimental and clinical studies are needed a conversely,under specific active conditions synapses (conditionallyappear to be rapidly silent silenced synapses) in many [4,5]. instances. Their recruitment to physiological effectiveness may be Introduction Epilepsy is a chronic neurological disorder characterized by an important The conversion component mechanism of circuit modification.included:(1) postsynaptically recurrent (two or more) unprovoked or spontaneous seizures

AMPA receptor insertion [4];(2) presynaptic transmitter due to abnormal hyperexcitable, hypersynchronous neuronal monophosphate)releasing:BDNF-Cdc42(brain signal pathway[5]. derived All neurotrophic previous mentioned factor-) population activity. This disease is extremely dangerous and genessignaling and proteins [6]; Calcium were abnormal influx [7];in epilepsy cAMP(Cyclic patients and Adenosine animal Theselife threatening. different ideas However, regarding the mechanisms seizure have of epilepsybeen suggested and the models. Activity-dependent modulation of synaptic function and neural consequences of epileptic neuronal activity were unclear. structure is emerging as one of the key mechanisms in epilepsy neurotransmission [1,2]. treatment (Figure 1). as previous study including excitatory or inhibitory synaptic glutamatergicIn the central synapse nervous whose systems postsynaptic (CNS), synapses membrane can be contains divided into silent and functional synapse.A silent synapse is an excitatory typeNMDA-type(N-methyl-D-aspartic glutamate receptors. Functional acid) synapse glutamate would receptors have all but its normalno AMPA(α-amino-3-hydroxyl-5-methyl-4-isoxazole structural components, and also poses an propionate)-appropriate complement of the essential presynaptic molecules and postsynaptic receptors. Some synapses appear “silent” in young or old animal and

Itpeople can been brain transformed regions [3], intosuch activated as hippocampus, synapse containingcerebral cortex, both the spinal cord. Silent synapses contain only NMDA receptors.

NMDA and AMPA receptors within minutes by simultaneous thatpresynaptic do not andproduce postsynaptic a physiological depolarization response [4]. inSilent the synapses,receiving defined as structural specializations for neurotransmission Figure 1: The pathway and mechanism of silent synapse in epilepsy. include incompletely assembled synapses that lack structural cell, may occur frequently in neural circuits. Silent synapses and nonfunctional postsynaptic receptors, or presence of BDNF: Brain Derived Neurotrophic Factor; TrkB: Camp Cyclic components, insufficient availability of key presynaptic proteins, Adenosine Monophosphate; PKC: Protein Kinase C; AMPA: α-amino-3- hydroxyl-5-methyl-4-isoxazole propionate receptors that do not mediate a postsynaptic response except

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receptors or ion channels by altering phosphorylation. In some 2+ A seizure is the result of an excessive discharge of hyper 2+ excitable cerebrocortical neurons. Mechanisms of neuronal neurons, Ca influx contributes to spikerepolarization and after- hyper excitability were caused by ion channel citations, increased hyperpolarizations [23,24]. Ca induced genetic expression can be transmissionexcitatory synaptic occurs at neurotransmission, glutamatergic synapses decreased and is inhibitorymediated mediated by cAMP-response element binding protein (CREB), the neurotransmission. In the CNS the majority of excitatory synaptic abnormalactivation inof epilepsytranscription patients factor and CREB animal requires models. phosphorylation In vitro studies, induced by CaMKIIα [20]. All previous proteins and genes were via the AMPA, NMDA, and kainate-type glutamate receptors [8- 2+]i in cultured rat cortical neurons [13]. activity,10]. Experimental whereas their studies antagonists using animalsuppress epilepsy seizure modelsactivity have[11- perampanel potently inhibited AMPA-induced increases in 15].shown that NMDA, AMPA and kainite agonists induce seizure intracellularcAMP [Ca

Silent Synapse and LTP increase in transmitter release at many central synapses by cAMP is a classic second messenger. It can elicit a long-lasting areModels believed of to synaptic underlie plasticity, the seizure such occurrence as long-term in the potentiation adult brain activating cAMP-dependent protein kinase (PKA) [21,23]. PKA is and(LTP) the and activity-dependent long-term depression regulation (LTD) of of glutamatergic synapse formation synapses, in believed to be a major modulator of synaptic transmission and underlie long-term potentiation of synaptic efficacy in epilepsy ligand- activated cation channels that mediate the fast component and enhance the release of transmitters and hormones [8,16,17]. developing brain [16]. Glutamate receptors sensitive to AMPA are Previous study also found that the activity of PKA was increased both in neocortex and hippocampus of epilepsy patients and mayof excitatory play a role postsynaptic in epileptogenesis currents and in in neurons seizure-induced of the central brain animalBDNF-CDC42 models [27]. signaling pathway nervous system. There is emerging evidence that AMPA receptors A novel mechanism underlying activity-induced rapid presynaptic maturation of silent synapse was induced by damage [8]. Efforts targeting AMPAR, such as perampanel [13] asCPP[17], potential dizocilpine therapeutic [14], agents D-2-amino-5-phosphonopen- useful in the prevention tanoate and [6]. This rapid presynaptic maturation can be abolished by treatment(AP5) [18] of have a variety been focused of neurological on the identification and non-neurological of ligands treatmentsactivation of BDNF BDNF-CDC42 inhibitor whilesignaling BDNF at canpresynaptic promote releasethe synaptic sites diseases [11,12]. The phencyclidine and ketamine were identiied rapidly maturation. The mechanism might be increased the as channel-blocking (uncompetitive) NMDA receptor antagonists presynaptic glutamate release and actin polymerization. Kindled Presynapticin the epilepsy Silenttreatment Synapse [19]. Activation in Epilepsy seizures dramatically increased expression of BDNF and TrkB in The molecular mechanisms underlying activation of epilepsythe dentate patients gyrus compared [28], mossy with ﬁber the controlaxons [29]. tissue In [30]. our previous presynaptic silent synapses and their contribution to long- study, we also found that CDC42 was higher in the brain tissue of term synaptic plasticity are widely unknown. The activation of presynaptic silent synapses is dependent on calcium [20- BDNF is required for the induction of a presynaptic component of the functional conversion, of silent synapses [24]. decreasesOver-expressed the inhibition BDNF in associated the brain and with induces this LTP up-regulation in epileptic of 22], cAMP-dependent protein kinase [21,23], and BDNF-Cdc42 TrkBpatients receptors, and animal which models in turn [24,31] trigger increases many downstream the excitation signals. and signalingCa2+ influx [6,24]. BDNF probably modulates GABAA receptors through mechanisms

Presynaptic LTP of synaptic transmission2+ activates silent isinvolving the downstream PKC phosphorylation. pathway of BDNF-TrkB BDNF binding signaling to TrkB in mediatingresults in synapses2+ and potentiates existing active synapses. Calcium is a activity-receptor dependent dimerization, presynaptic enhanced maturation activity of the and CDC42 plasticity [32] [6]. CDC42 The major signaling molecule in neurons. Ca influx through the L-type Ca channels2+ role is inmuch epileptogenesis greater in the remains CA3 area elevated of spontaneously and initiates might be actin cytoskeleton remodeling, and then induce the manyepileptic second rat than messenger in that of normal effects animals that [7].produce During long-lasting the latency mechanism of Cdc42 induced rapid conversion of silent synapses phase, Ca 2+ in andtrafﬁcking protein isor obviouslyscaffolding increased of vesicles in aor seizure key exocytosis of multiple molecules animal pentylentetrazol-inducedplasticity changes in these epilepsy neurons of [7,10]. rats [10]. Topiramate modulates modelsto the presynaptic and the hippocampus terminal [6]. TrkB.of humans Expression with oftemporal BDNF mRNA lobe hippocampus NMDA receptors via the increased neuronal Ca 2+ of BDNF enhance limbic epileptogenesis [32]. 2+, activates many calcium- epilepsy. Administration of BDNF and transgenic over expression Ca is known as the primary mediator of “excitotoxic” neuronal damage. Increase of concentration of Ca Postsynaptical Silent Synapses Activation in Epilepsy dependent enzymes, including CaMKIIα [25], protein kinase C neurotransmitters(PKC) [26], nitric oxiderelease synthase from presynaptic (NOS), and sites, various and proteasesneuronal and endonucleases, gene and protein expression [22,23], an Postsynapticallyimportant role in silent constructing synapses neuronal and their microcircuits conversion [33]. into structural proteins, and may modify the functions of enzymes, functional ones via AMPA receptor trafficking mechanisms play excitable regulation. These enzymes may have direct effects on AMPARs inserted during the induction of LTP and removed

Citation:

Xi ZQ, Wang XF, Hu Y, Zeng K (2016) Silent Synapse Activation in Epilepsy. J Neurol Stroke 5(2): 00174. DOI: 10.15406/jnsk.2016.05.00174 Copyright: Silent Synapse Activation in Epilepsy ©2016 Xi et al. 3/4

during induction of LTD are depended on GluR1(glutamate the postsynaptic membrane, and GluR2-containing receptors 8. Porter BE, Cui XN, Brooks-Kayal AR (2006) Brooks Kayal, Status receptor)-associated processes that stabilize AMPARs within epilepticus differentially alters AMPA and kainate receptor subunit expression in mature and immature dentate granule neurons. Eur J state, respectively, by the postsynaptic density scaffold proteins Neurosci 23(11): 2857-2863. processes that adjust AMPAR trafficking in the active and silent 9. Rakhade SN, Zhou C, Aujla PK, Fishman R, Sucher NJ, et al. (2008) importantPICK and GRIP in synaptic[34]. Glutamate transmission, receptor plasticity, channels mediateand protein– most Early alterations of AMPA receptors mediate synaptic potentiation 10. induced by neonatal seizures. J Neurosci 28(32): 7979-7990. proteinexcitatory interactions transmission in seizure at synapses occurrence in the brain,[35]. GluR1 and are and critically GluR2 2+ are abundantly distributed in the neuronal layers of hippocampus homeostasisYilmaz M, Naziro in pentylentetrazol-inducedğlu M, Kutluhan S, Yilmaz N,epilepsy Yürekli of VA, rats. et al. J (2011)Recept hippocampus and changed in posttraumatic epilepsy [36], in the Topiramate modulates hippocampus NMDA receptors via brain Ca

11. Signal Transduct Res 31(2): 173-179. WAG/Rij rat model of absence epilepsy [37]. Glutamate receptor Rogawski MA, Donevan SD (1999) AMPA receptors in epilepsy and as areantagonists abnormal protects in epilepsy against patients seizure-induced and animal model, excitotoxic therefore cell 12. targets for antiepileptic drugs 79: 947-963. death in the brain [38]. Previous mentioned proteins and genes we speculated that epilepsy is associated with postsynaptic silent De Sarro G, Gitto R, Russo E, Ibbadu GF, Barreca ML, et al. (2005) synapses activation. AMPA receptor antagonists as potential anticonvulsant drugs. Curr 13. Top Med Chem 5(1): 31-42. Conclusion receptorHanada T, antagonist Hashizume that Y, reducesTokuhara seizure N, Takenaka activity O, in Kohmura rodent models N, et al.of There is a substantial body of evidence from basic research (2011) Perampanel: A novel, orally active, noncompetitive AMPA that indicate an important role of silent synapse activation in epilepsy pathogenesis. The activation included postsynaptical epilepsy. Epilepsia 52(7): 1331-1340. and presynaptic silent synapses. Taken these results together, 14. Rogawski MA (2011) Revisiting AMPA Receptors as an Antiepileptic it is reasonable to purpose that silent synapse conversion 15. DrugNgomba Target. RT, SantoliniEpilepsy CurrI, Salt 11(2): TE, Ferraguti 56-63. F, Battaglia G, et al. (2011)

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Citation:

Xi ZQ, Wang XF, Hu Y, Zeng K (2016) Silent Synapse Activation in Epilepsy. J Neurol Stroke 5(2): 00174. DOI: 10.15406/jnsk.2016.05.00174