Yu Tian Wang

Professor

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
The role of hippocampal long-term depression in novel spatial exploration (2018)

The exploration and encoding of a novel environment is a fundamental learning process that occurs on a short time scale, and is a useful model for studying how the hippocampus encodes and represents complex and arbitrary associations, as is required for episodic memory. Novelty exploration has been demonstrated to promote long-term depression (LTD) induction in area CA1 of the hippocampus, but it is unclear what role this LTD plays as the novel space becomes familiarized and encoded in the hippocampus.In order to determine whether de novo LTD occurs during novelty exploration, we utilized multi-array electrophysiological recording in freely moving rats and demonstrated an AMPA receptor endocytosis-dependent LTD in CA1 in the absence of a paired LTD induction protocol. To determine what role this LTD played in forming spatial representations, we recorded the spiking activity of multiple single units in hippocampal CA1 using multi-tetrode electrophysiological recordings to observe the development of place field firing in a novel environment, and the effect of LTD blockade using an inhibitor of AMPAR endocytosis. Place fields formed in the presence of LTD blockade, however the maintenance of place field firing location between the novel environmental exposure and re-exposure one day later was impaired by inhibition of LTD.To investigate the dynamics of place field formation over the first several minutes of exposure, hippocampal neurons were recorded during exposure to a novel linear environment. While fields developed and stabilized over several minutes in control rats, we found that LTD blockade produced a rapid establishment of stable place fields after a single lap, suggesting the dynamics of field formation are altered with LTD blockade.To test the role of this LTD in novel spatial learning, the effect of LTD blockade on contextual fear was assessed using a modification of inhibitory avoidance training that separated the acquisition of contextual information from the pairing with an aversive stimulus. This demonstrated that LTD is required on the first exposure to a novel context.These results place the activity dependent weakening of synapses as a central process in the rapid acquisition of novel spatial information in the hippocampus.

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Development of a small alpha-synuclein-knockdown peptide as a potential therapy for Parkinson’s disease (2016)

Accumulating evidence supports the premise that reducing α-synuclein levels may be an effective and specific therapy for Parkinson’s disease. To date, a clinically applicable α-synuclein reducing therapeutic strategy has yet to be developed. To remedy this, I developed a blood brain barrier and plasma membrane-permeable α-synuclein knockdown peptide that may have therapeutic potentials. By modifying a peptide-based method that was recently developed in our lab to rapidly and reversibly decrease the levels of endogenous proteins, I developed an α-synuclein knockdown peptide, Tat-βsyn-degron, and tested its specificity and efficacy in reducing the level of α-synuclein and its neuroprotective efficacy in well-characterized cellular and animal models of Parkinson’s disease. I found that the peptide effectively reduced the level of α-synuclein via proteasomal degradation both in cell cultures and in freely moving animals. More importantly, the peptide-induced α-synuclein reduction was associated with a significant decrease in parkinsonian toxin-induced neuronal damage and motor impairment in an animal model of Parkinson’s disease. These results suggest that targeted degradation of α-synuclein using the Tat-βsyn-degron peptide represents a novel, specific and effective therapeutic strategy for reversing a core cellular mechanism contributing to Parkinson’s disease.

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Discovery of a selective GluN2A-containing N-methyl-d-aspartate glutamate receptor positive modulator as a novel post-stroke neuroprotective therapy (2016)

N-methyl-d-aspartate glutamate receptors (NMDARs) are fundamental to many normal brain functions such as cognition and memory; however, NMDAR over-activation can cause neuronal death as a result of excitotoxicity. Although the mechanisms underlying these paradoxical roles of NMDARs remain unclear, accumulating evidence from both in-vitro and in-vivo studies suggested that GluN1/GluN2B-NMDAR subtypes mediated signaling may contribute cell death, while GluN1/GluN2A-NMDARs signaling promote pro-survival outcomes. Employing an extensive drug discovery pipeline process, we identified and characterized a class of novel small molecules that specifically potentiate GluN1/GluN2A NMDARs in an allosteric manner. This new class of molecules is referred to as NMDAR positive allosteric modulators (Npams) with the Npam43 being the lead compound. Mutational analysis demonstrates that Npam43 binds to a novel binding site on the N-terminal domain (NTD) at the interface between the GluN1 and GluN2A subunits. Functional characterizations in in-vitro show that Npam43 activates cell survival signaling, increasing phosphorylated CREB levels, and thereby protects neurons against NMDAR-mediated excitotoxicity and NMDA-independent H₂O₂ oxidative stress. Moreover, Npam43 potentiates GluN1/GluN2A-mediated synaptic currents, and facilitates the induction of long-term potentiation (LTP) in hippocampal slices acutely prepared from mouse brain. Using a rat focal ischemia model of stroke in-vivo, we show that systemic administration of Npam43 not only modulates GluN1/GluN2A containing NMDARs but also substantially reduces neuronal damage and improves behavioral outcomes. Together, our study not only develops a novel class of Npams for GluN1/GluN2A NMDARs, but also demonstrates their therapeutic potential as novel neuroprotectants for stroke. In addition, the present work also provides strong evidence supporting a critical role of GluN1/GluN2A subtype of NMDARs in promoting cell survival.

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Identification and characterization of a novel allosteric glutamate binding site on the GABA-A receptor (2016)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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Novel, peptide-mediated neuroprotective strategies for Huntington's Disease (2016)

Huntington’s disease (HD) is an inherited neurodegenerative disease with progressive striatal loss. No treatments exist, though availability of predictive testing offers possibility for early intervention. Peptides represent an exciting way to interact with molecular signaling. My thesis investigates three potential early targets for preventative HD therapies: NMDAR-mediated PTEN nuclear translocation, caspase-6 activation, and peptide-mediated mutant huntingtin (mHTT) knockdown. Excitotoxicity via N-methyl-D-aspartate receptor (NMDAR) over-activation has a role in HD pathogenesis. We recently demonstrated that nuclear translocation of phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a critical step in NMDAR-mediated excitotoxicity, and blocking PTEN nuclear translocation with peptide Tat-K13 prevents excitotoxic neuronal death. Given the role of NMDAR-mediated excitoxicity in HD, PTEN nuclear translocation may have a role in excitotoxic neuron death in HD. Here, PTEN nuclear translocation was associated with NMDAR-mediated death in cultured HD neurons. I also detected small increases in nuclear PTEN in HD transgenic mouse brains vs control. Interestingly, Tat-K13 effectively blocked PTEN translocation and prevented excitotoxicity in cortex/hippocampus, but not striatum, in vitro and in vivo, suggesting differential mechanisms of PTEN nuclear translocation. Caspase activation downstream of NMDARs may be critically involved in excitotoxicity. Caspase-6 (casp6) particularly, has roles in pathogenesis of HD and other conditions. Using NMDA-induced excitotoxicity in cultured neurons, I demonstrated early increase in caspase profiles via mRNA, protein and activity. Casp6 is elevated and activated first, followed by caspase-8 and caspase-3. Casp6 substrate huntingtin, and novel casp6 substrates STK3 and DAXX, are cleaved in similar temporal patterns post-NMDA, pointing to casp6 is an initiator caspase in NMDA-mediated apoptotic cascades and a potential therapeutic target. Many studies suggest that reducing mHTT protein may be an effective HD therapy. Our lab recently developed a technique for targeted protein degradation using peptides that signal proteins for lysosome- or proteasome-mediated degradation. Utilizing mHTT-binding domains paired with degradation sequences, I designed and tested mHTT-degradation peptides. In cultured neurons from HD transgenic mice, mHTT-degradation peptides led to robust mHTT knockdown, at least in part due to degradation. mHTT degradation peptides were ineffective in vivo, but pointed to potential for development of peptide-mediated mHTT-lowering therapies.

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Harnessing chaperone-mediated autophagy for the degradation of endogenous proteins (2015)

Rapid and reversible methods for altering the function of endogenous proteins are not only indispensable tools for probing complex biological systems, but may potentially drive the development of new therapeutics for the treatment of human diseases. Genetic approaches have provided insights into protein function, but are limited in speed, reversibility and spatiotemporal control. To overcome these limitations, we have developed a peptide-based method to degrade a given endogenous protein at the post-translational level by harnessing chaperone-mediated autophagy, a major intracellular protein degradation pathway mediated by the lysosome. This thesis presents the design and validation of SNIPER (Selective Native Protein ERadication) for use in cultured cells as well as in intact animals. Specifically, we demonstrate the specificity, efficacy and generalizability of SNIPER by showing efficient knockdown of various proteins, including death-associated protein kinase 1 (160 kDa), scaffolding protein PSD-95 (95 kDa) and α-synuclein (19 kDa), with their respective SNIPER peptides in cell lines and rat neuronal cultures. Moreover, we examine the characteristics of SNIPER-mediated protein knockdown and found that the level of protein knockdown is dose-, time- and lysosome-dependent. Furthermore, we demonstrate that SNIPER efficiently knocked down a dephosphorylated subpopulation of a given protein while sparing its phosphorylated form, attesting to the specificity of the method. Finally, using a rat model of focal ischemic stroke, we show that a single intravenous injection of a SNIPER peptide efficiently knocked down a death-promoting protein in the brains of freely moving rats and protected the rat brain from ischemic injury. Taken together, SNIPER is a robust and convenient research tool for manipulating the levels of endogenous proteins in situ, and may also lead to the development of novel protein knockdown–based therapeutics for treating human diseases.

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Developing novel therapeutics for excitotoxic neuronal death following stroke (2011)

Ischemic stroke is a major cause of death and disability in developed countries, and a major economic burden in the world. The mechanisms mediating stroke damage are likely multifactorial, with N- methyl-D-aspartate receptor (NMDAR) mediated excitotoxicity being an important factor. But NMDAR blockers are not clinically feasible due to their side effects and short therapeutic window. This doctoral dissertation discusses an ongoing effort to develop novel anti-excitotoxic therapeutics that can overcome these limitations. Our strategies are largely based on the premises that NR2A- subunit containing NMDARs (NR2ARs) are pro-survival whereas NR2B-subunit containing NMDARs (NR2BRs) are pro-death, and NR2BRs mediate neuronal death in large by activating a set of neuronal death signaling proteins.Specific Findings: 1, we investigated whether stimulation of NR2ARs by the NMDAR co- agonist glycine rather than blocking NR2BRs would confer a wider therapeutic time window in an in vivo rat model of focal and global ischemia. Because we stimulated neuronal survival rather than blocked neuronal death, our therapeutic remained efficacious up to 6 h post-ictus - a time point when many known death signaling proteins downstream of NR2BRs were already activated. 2, we studied the death-signaling pathway of SREBP1 (sterol response element binding protien 1), a transcription factor downstream of NR2BR, in an in vivo rat model of focal ischemia. In the ischemic brain, we found SREBP1 activation and nuclear translocation due to the ubiquitination and degradation of its inhibitory partner Insig1 (protein encoded by insulin signaling gene1). Notably, the new therapeutic peptide Indip (Insig1 degradation inhibiting peptide) prevented neuronal death when administered 1 h pre- and 2 h post-ictus. Because we targeted a death-signaling protein rather than all signaling proteins downstream of NMDARs, our treatment would have fewer side effects than NMDAR blockers. 3, we developed a novel method to selectively knockdown death-signaling proteins downstream of NR2BRs by means of ubiquitin-tagged peptides. Because interference peptides in the past were limited to disrupting protein-protein interactions and post-translational modifications, this opened a new avenue to develop therapeutics for excitotoxicity following stroke.

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Neural stem cell transplantation : neuroprotection and LTP-induced facilitation of neurogenesis (2011)

Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in the Alzheimer’s disease (AD) brain are largely unknown and a primary objective of this work is to demonstrate possible efficacy of NPC administration in an AD animal model. The benefits of transplantation could involve a spectrum of effects including replacement of endogenous neurons, conferring neuroprotection with enhancement of neurotrophic factors, and diminishing levels of neurotoxic agents. Additionally, since chronic inflammation is a characteristic property of the AD brain, I considered NPC transplantation could have a particular utility in inhibiting ongoing inflammatory reactivity. Accordingly, intra-hippocampal transplantation of NPC has been examined for efficacy in attenuating inflammatory responses and conferring neuroprotection in the hippocampus. These findings indicate efficacy for NPC transplantation with effects consistent with cellular actions to attenuate inflammatory reactivity. Synaptic plasticity, such as long-term potentiation (LTP), is thought to play a critical role in modification of neuronal circuitry in learning and memory, but the role in neurogenesis is not well known. A critical aspect of my study was to examine potential roles of N-methyl-D-aspartate receptor (NMDAR)-dependent LTP in promoting neurogenesis by facilitating proliferation/survival and neuronal differentiation of endogenous NPCs in the dentate gyrus (DG) and exogenously transplanted neural stem cells (NSCs) in the CA1. I found that LTP induction significantly facilitates proliferation/survival and neuronal differentiation of endogenous NPCs and exogenously transplanted NSCs in the hippocampus. These effects were eliminated by a NMDAR competitive antagonist, CPP. Accordingly, chemical LTP stimulation reproduced enhanced proliferation/survival and neuronal differentiation of NSCs when co-cultured with hippocampal neurons. These effects were eliminated by a NMDAR competitive antagonist, D-APV and inhibited by the tyrosine kinase inhibitor, K252a. ELISA and biotinylation results revealed that NMDAR-mediated LTP facilitates the release of a neurotrophic factor, BDNF. The conditioned media from cLTP-induced hippocampal neurons were sufficient to activate the BDNF receptor, TrkB. Overall, my results suggest that NMDAR-dependent LTP plays a critical role in neurogenesis and may contribute to the utility of NSC transplantation as an effective cell therapy for a variety of neurodegenerative diseases.

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Role of PTEN nuclear translocation in excitotoxic and ischemic neuronal injuries following stroke (2011)

Stroke is a leading cause of death and disability in developed countries. About 87% of stroke cases results from blood vessel(s) occlusion in the brain, leading toneuronal death and neurological impairment (Lloyd-Jones et al., 2010). The ischemic progression likely involves multiple events, and increasing evidence showed that the ischemic neuronal death is caused, at least in part, by over-activation of N-methyl-Daspartate subtype glutamate receptors (NMDARs) (Rothman, 1983, Rothman, 1984, Simon et al., 1984). A large number of pre-clinical studies showed that NMDAR antagonists have strong neuroprotective effects against ischemic insults (Park et al.,1988b, Bullock et al., 1990). However, none of the following human clinical trials have succeeded yet (Muir, 2006). Several explanations have been suggested (Gladstone et al., 2002), including the following two major reasons that may beovercome by the novel therapeutics proposed here. First, the stroke patient inclusion periods (>6 hours) used by most clinical trials are beyond the therapeutic time window (
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Mechanisms underlying the epileptic pheotype associated with the alpha-1 A322D mutation in the GABE-A receptor (2010)

No abstract available.

Modulation of AMPA receptor trafficking and its involvement in synaptic plasticity and spatial memory (2010)

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) subtype of glutamate receptors mediates the fast excitatory synaptic transmission in the mammalian brain. Increasing evidence suggests that rapid movement of AMPARs into and out of synapses is the major mechanism for changes in synaptic strength, which is thought to underlie learning and memory. Although the bidirectional hippocampal synaptic plasticity, particularly long-term potentiation (LTP) and long-term depression (LTD), has been regarded as a candidate mechanism for long-term spatial memory (LSM), the precise contribution of LTP and LTD to LSM remains poorly understood. Using antagonists that target NMDARs carrying specific NR2 subunits, we found that LTP and LTD in freely moving rats can be selectively abolished by NR2A and NR2B antagonists, respectively. Using the Morris water maze, we found that only the NR2B antagonist disturbed the consolidation of LSM. In addition, a similar LSM deficit was observed when the expression of LTD was prevented by inhibiting regulated AMPAR endocytosis. Thus, these findings support a functional requirement of hippocampal LTD in the consolidation of LSM. Blocking LTP by NR2A-preferential antagonist had no effects on LSM. However, another structurally and mechanistically different LTP-specific inhibitor is still lacking. Since the expression of LTP is thought to be mediated by the facilitated exocytosis of AMPARs, we therefore attempted to identify novel AMPAR binding partner(s) using co-immunoprecipitatoin with anti-GluR1 or anti-GluR2 antibody followed by mass spectrometric analysis. We found that p97, also called valosin-containing protein (VCP), specifically interacts with and modulates trafficking of homomeric GluR1 receptors. Using various truncated and deleted constructs of GluR1, we found that p97 interacts with N-terminal of GluR1, but not GluR2, resulting in facilitated formation of homomeric GluR1 receptors by decreasing GluR1/GluR2 heteromeric receptors formation. Moreover, we found that under basal conditions, p97 retained homomeric GluR1 AMPARs in the intracellular pool, but immediately after the induction of LTP, it disassociated from GluR1 and hence, allowed these homomeric AMPARs insert into the postsynaptic membrane, thereby contributing to LTP expression. Thus, our results highlight a previously unknown molecular mechanism by which p97 regulates formation and trafficking of homomeric GluR1 AMPARs, and thereby plays a critical role in LTP expression.

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Modulation of ligand-gated receptors in the central nervous system (2010)

Basal level neuronal excitability in the mammalian brain is fundamental for physiological brain functions. It is primarily maintained by a fine balance between two types of synaptic transmission: the excitatory transmission mediated by glutamate-gated ion channels including α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPARs) and N-methyl-D-aspartic acid receptors (NMDARs), and the inhibitory transmission mediated by chloride channels including γ-Aminobutyric acid receptors (GABAARs) found in the brain and glycine receptors (GlyRs) orginating in the spinal cord and brainstem. Therefore, understanding mechanisms by which these ligand-gated ion channels (LIGCs) are regulated is critical for our understanding of both brain functions and dysfunctions, and is the major focus of this thesis. In particular, this research project investigates: 1) how rapid alteration of AMPAR trafficking results in changes in strength of synaptic transmission, with a particular emphasis on its contribution to amygdala long-term potentiation (LTP) and depression (LTD), the two most well-characterized forms of synaptic plasticity, and 2) how excitatory transmitter glutamate modulates functions of the inhibitory GABAA and Gly receptors. In chaper 2 and 3, we show in lateral amygdale (LA) slices that the induction of LTP requires NR2A-containing NMDAR activation, while the expression of LTP requires AMPARs insertion (sensitive to TeTx or GluR1-derived peptide). On the contrary, the induction of LTD involves activation of NR2B-containing NMDARs and the expression of LTD involves AMPARs endocytosis (sensitive to GluR2-3Y peptide). The inhibitory receptors GABAARs and GlyRs are respectively activated by binding with their respective transmitters, GABA and glycine. In chapter 4 and 5, we show novel and unexpected findings where glutamate potentiates currents mediated by either GABAARs or GlyRs in neurons and in HEK cells over-expressing recombinant GABAARs and GlyRs. This potentiation was not dependent on activation of any known ionotropic or metabotropic glutamate receptors. Thus, our results strongly suggest that glutamate can allosterically potentiate the function of GABAARs and GlyRs, thereby blurring the traditional distinction between excitatory and inhibitory transmitters. Such a rapid homeostatic regulatory mechanism may have a significant role in tuning functional balance between synaptic excitation and inhibition in the central nervous system (CNS).

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Modeling neurodevelopmental disorders : expression of neuroligin adhesion molecules in vivo (2009)

At post synaptic sites, the neuroligin (NL) family of proteins is thought to play an important role in synapse maturation, and regulation of excitatory and inhibitory synapses. Being selectively enriched at either excitatory (NL1,3) or inhibitory (NL2) synapses, NL’s have been shown to regulate the ratio of excitation to inhibition (E/I ratio), a process critical for normal brain development. In addition, NLs have been linked to neurodevelopmental disorders through genetic studies. To advance our understanding of synaptic regulation by NLs, and their potential role in synaptic dysfunciton in neurodevelopmental disorders, we have developed strains of transgenic mice which overexpress either HA tagged-NL1, or -NL2 under control of the Thy1 promoter. Detailed behavioural analysis of TgNL2 mice revealed anxiety, stereotyped jumping behaviour, and impairments in social approach and reciprocal social interactions. These animals also displayed fronto-parietal seizure activity as shown by chronic in vivo EEG recording. Synapse analysis in TgNL2 frontal cortex revealed changes in the number and morphology of synapses compared to wildtype littermates. A small change in NL2 expression results in enlarged synaptic contact size and vesicle reserve pool and an overall reduction in the E/I ratio. In addition, the frequency of miniature inhibitory synaptic currents was also found to be increased in the frontal cortex of TgNL2 mice. Behavioural assessment of TgNL1 mice revealed deficits in memory acquisition and retrieval in water maze paradigms. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the E/I ratio towards increased excitation. Further experiments revealed impairment in the induction of long term potentiation.These data demonstrate that altered expression of members of the NL family in vivo leads to altered synapse number and morphology, which potentially underlies the profound behavioural changes. We also observed a predominant effect of NL2 expression on inhibitory synapses, with NL1 primarily influencing excitatory synapses, supporting the idea that NL’s may act to regulate the E/I ratio. In addition this data may provide insight into the pathology and symptoms of neurodevelopmental disorders such as autism thought be be caused by synaptic abnormalities.

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Master's Student Supervision (2010 - 2018)
Design and optimization of small peptides that regulate the balance of synaptic excitation and inhibition (2017)

The balance of synaptic excitation and inhibition plays a very important role in maintaining the function of central nervous system (CNS) and the imbalance is involved in neurologic diseases such as autism and epilepsy. PSD95 and gephyrin have been studied as scaffolding proteins, having critical functional and structural roles in excitatory and inhibitory synapses, respectively. In the thesis, I have attempted to develop small systemically applicable peptides that can reversibly knock down PSD95 or gephyrin in vitro and in vivo, using the novel peptide-mediated technology recently developed in our lab, as tools for modulating the balance of synaptic excitation and inhibition. The efficacy of the peptides knocking down respective targeted proteins was tested by immunoblots after the cultured neurons were treated with the peptides for the desired time at various concentrations. I found that peptides that target either PSD95 or gephyrin showed toxicity to the neurons in a dose and time dependent manner utilizing the LDH assay. The toxicity may also contribute to the reduction of protein levels. Using one of the peptides, TAT-NR2B9C-CMA that targets PSD95 as example, I systemically investigated the causes of the toxicity and tested several strategies to reduce the toxicity while keeping the efficacy of the protein knockdown. I found that while multiple treatments at low dose could not successfully separate the cell death and knockdown effect, treatment at high doses with shortened durations appeared partially effective in reducing the toxicity and maintaining knockdown efficacy. However, this protocol may not be applicable in vivo. I next modified the intrinsic properties of peptides by shortening CMA targeting motifs and/or adding a linker between the binding sequences and CMA targeting motif. I found that while both strategies could decrease the toxicity with varied degree, peptides with short CMA targeting motif kept the knockdown efficacy. Taken together, my study demonstrated the effective strategies to reduce the toxicity of the peptides one can consider in the process of developing novel protein knockdown peptides as novel research tools and therapeutic reagents.

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Screening for novel modulators of GABAA receptors (2013)

GABAA receptors are a family of ligand gated ion channels that play essential roles both in normal brain functions and psychiatric conditions. While the classical GABAA receptor modulators benzodiazepines have been in clinical use for decades and are still among the most widely prescribed drugs for the treatment of certain disorders, their limitations and side effects have been driving the search for alternative solutions. Recent studies from our lab have demonstrated that glutamate can act as positive allosteric modulators of GABAA receptors, and the suggested binding sites are on the interface of alpha and beta subunits. This surprising finding drove us to pursuit two objectives: (1) screen glutamate-like molecules that can compete with glutamate and prevent the potentiation of GABAA receptors, so we can study the intrinsic functions of the modulating effects of glutamate; (2) screen glutamate-like molecules that can mimic glutamate and potentiate GABAA receptors but do not produce any other physiological effects, so we can utilize them as candidates for clinical treatment as alternatives of benzodiazepines.Experiments are performed on hippocampal neuron cultures and HEK 293 cells transfected with GABAA receptor subunits. Virtual screening and electrophysiology recording are employed. For objective (1), we identified 10 compounds that can inhibit glutamate from potentiating GABAA receptor. Unfortunately, none of them can completely block the potentiation. For objective (2), we identified one compound, 2-methyl aspartic acid (2-MAA), as the final candidate for further study. We found that 2-MAA shares the binding sites with glutamate and potentiates GABAA receptors in a dose-dependent manner, while it does not affect normal neuronal activities. In addition, although it shows no significant effect on tonic GABA current amplitude, it does increase the frequency of mini-IPSCs. In the future, for objective (1), it will require screening for additional candidates and/or modification of the 10 compounds. For objective (2), we can continue testing the anti-epilepsy effect of 2-MAA on both in vitro and in vivo models. It will also be applicable to modify the compound or to screen similar compounds so as to get a better candidate with bigger potentiation at a lower concentration.

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