Contact us:

  Markus Kessler 

  Kyle Montgomery

  Yoshihiko Wakazono

  Erika Suzuki

  Yan-Fang Xia

  Nathane Orwig
 

Cellular and molecular function of AMPA receptors and neuropeptide receptors
Most excitatory synaptic transmission in the brain is mediated through AMPA-type glutamate receptors and thus changes in the properties of these receptors are likely to have a major impact on brain function. A main focus of our laboratory is on endogenous mechanisms and drugs which alter the kinetic properties of AMPA receptors and on the consequences of such receptor modulation for synaptic transmission and local network properties. A second focus is on the role of neuropeptides of the RF-amide family, in particular kisspeptin/metastin and PrRP (prolactin-releasing peptide), in regulating synaptic and cellular physiology in the hippocampus, amygdala and thalamus.
 
  

organotypic slice culture

or 

Department of Pharmacology
SIU School of Medicine
Room 3321 (office) 

or Room 3275 (laboratory)
Mail code 9629
801 N. Rutledge Street
Springfield IL 62702

Tel: 217-545-2204 (Laboratory)
Tel: 217-545-0228 (Arai Office)
FAX: 217-545-0145

New publications:

Review article:
Arai AC and Kessler M (2007) Pharmacology of Ampakine modulators: From AMPA receptors to synapses and behavior. Current Drug Targets, 8: 583-602. 

Original articles:
Suzuki E, Kessler M, Arai AC (2008) The fast kinetics of AMPA GluR3 receptors is selectively modulated by the TARPs gamma-4 and gamma-8.
Mol Cell Neurosci. in press. 

Kessler M, Suzuki E, Montgomery K, Arai AC.(2008) Physiological significance of high- and low-affinity agonist binding to neuronal and recombinant AMPA receptors.  Neurochem Int.

Wu Y, Arai AC, Rumbaugh G, Srivastava AK, Turner G, Hayashi T,  Suzuki E, Jiang Y, Zhang L, Rodriguez J, Boyle J, Tarpey P, Raymond FL, Nevelsteen J, Froyen G, Stratton M, Futreal A, Gecz J, Stevenson R, Schwartz CE, Valle D, Huganir RL, Wang T (2007) Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc. Natl. Acad. Sci. USA, 104: 18153-18168. 

Arai AC, Xia Y-F, Suzuki E, Kessler M, Civelli O, Nothacker H-P. (2005) The cancer metastasis suppressing peptide metastin upregulates excitatory synaptic transmission in hippocampal dentate granule cells. J. Neurophysiol, 94: 3648-3652. 

1-BCP
CX516 (BDP-12)
BDP-20 (CX554)
CX546
CX614
IDRA-21
D-1
cyclothiazide
GYKI
aniracetam
thiocyanate
suramin/PPNDS
 

Pharmacology Home

SIU Home

AMPA receptor modulators are compounds which potentiate the effects of the endogenous transmitter glutamate. Earlier collaborations with chemists resulted in new compounds of this kind, called Ampakines. We have shown that selective enhancement of AMPA receptors by these drugs facilitates the formation of long-term potentiation (LTP), a cellular mechanism believed to be responsible for memory encoding. Others have shown that these compounds, as predicted, improve many types of memory in animal tests.  Some of these compounds are currently examined in clinical trials for their use against Alzheimer's disease and schizophrenia. On our part, we continue investigating how different subtypes of these modulators influence AMPA receptor kinetics, synaptic transmission, and synaptic plasticity.  

Other research themes:

Neuropeptides

KiSS-1/GPR54 

RF-amide Peptide Receptors

Synaptic plasticity
Hippocampal interneurons
Thalamic synaptic transmission
Calpain & Ischemia
Multielectrode recording
Cerebellum

 

Positive Modulation of  AMPA Receptors:  Effects on Synaptic Transmission,  Plasticity and Networks
AMPA receptor function differs across brain regions, mainly due to variation in subunit composition, but also because of differences in the characteristics of synapses and local circuits.  Depending on such properties, AMPA receptor mediated synaptic currents may be sharp or slow, may or may not be associated with calcium influx, and may exhibit either paired-pulse facilitation or paired-pulse depression, and there is much evidence that these differences are relevant for brain function and ultimately for behavior. The AMPA receptor modulators described above are a novel and enormously useful tool with which we can examine many aspects of this diversity in AMPA receptor mediated signaling. We are currently conducting such studies in which we compare properties of synaptic transmission between hippocampus, thalamus and inferior colliculus, and among cell types within these structures, using whole-cell recording in brain slices.

Kinetic Properties of AMPA Receptors 
The kinetic properties of AMPA receptors evidently are critical for determining the waveform of synaptic currents, but the relationship between them is not yet entirely clear. There is also evidence that AMPA receptors may exist in different ‘affinity states’ and that homomeric recombinant receptors differ from brain receptors in their kinetic properties. One of our main goals is to compare the kinetics of recombinant receptors and native AMPA receptors in synapses and in membrane patches excised from hippocampal slices, and to integrate kinetic data from physiological recordings with those from ligand binding assays. Experimental data are then compared with simulations using kinetic receptor models.
Receptor binding & Physiology correlation related publication

Paired application of 1-ms pulses to the AMPA receptor in a membrane patch excised from a pyramidal cell in the hippocampal CA1 field.  The amplitude of the second response is reduced because of receptor desensitization.

Role of Kisspeptin/GPR54 in the Limbic System
KiSS-1 was originally discovered in melanomas as a gene that prevents metastasis. More recent studies revealed that its gene product kisspeptin, also called metastin, is a ligand for the G-protein coupled receptor GPR54 which had been classified earlier as an orphan receptor. These studies further showed that the receptor is also highly expressed in several brain regions, in particular the hypothalamus, the amygdala and the dentate gyrus of the hippocampus. In the hypothalamus, the KiSS-1/GPR54 system has recently been shown to be critical for regulating reproduction, such as for the onset for puberty, but little is known about its role in the other two regions which are mainly involved in emotion and cognition. In the first study to address this question, we have recently shown that kisspeptin greatly increases excitatory synaptic transmission in dentate gyrus granule cells and that it does so through postsynaptic GPR54 and through signaling mechanisms that involve calcium-calmodulin kinase, tyrosine kinases, and the MAP kinases ERK1/2. Future goals of this project are to determine in greater detail how the KiSS-1/GPR54 system modulates the physiology of hippocampal and amygdala neurons, how it influences synaptic plasticity at their synapses, what its impact is on the cell biology of these neurons, and ultimately what the role of the KiSS-1/GPR54 system is in the behavioral function of the limbic system.  

Receptors for Prolactin-releasing peptide (PrRP) Regulate Thalamic Function
The prolactin-releasing peptide (PrRP) receptor is highly expressed in the reticular nucleus of the thalamus (RNT), but its role in the function of this brain region is not yet understood.  The RNT controls the flow of information from the senses through the thalamic nuclei to the cortex and it is believed to be important, for instance, for regulating sleep and attention. In a recent study we have shown that application of PrRP to thalamic slices suppresses oscillatory activity that resembles the slow-wave discharges seen during sleep, and that i.c.v. injection of this peptide reduces EEG seizures in an animal model for absence seizures. This suggests that drugs acting on this receptor may some day be of use to control various thalamic functions and the associated disorders.  Currently, our main interest is to investigate how PrRP receptors influence the physiology of the principal neurons in the RNT, and which intracellular signaling pathways are activated by the PrRP receptor.
Prolactin-releasing peptide (PrRP) receptor
 

Long-term changes in hippocampal physiology: in vitro studies using cultures grown on a 8x8-electrode array.
Pathological insults such as ischemia can lead to delayed neuronal degeneration days after the initial event. Processes involved in such degeneration have until now been mainly studied with biochemical methods. The recent development of culture dishes with an embedded electrode array now makes it possible for the first time to look in an in vitro preparation for long-term physiological changes that may be involved in neuronal degeneration and/or recovery. Using this system, we currently examine how physiological activity in slice cultures from hippocampus, cerebellum, and other brain regions changes after treatment with excitotoxic and other agents, and we monitor how activity recovers on the days after the initial treatment.
 

Arai AC, Xia Y-F, Suzuki E (2004) Modulation of AMPA receptor kinetics differentially influences formation of synaptic plasticity in the hippocampus. Neuroscience 123: 1011-1024. 

Arai A, Kessler M, Rogers G, Lynch G (1996) Effects of a memory enhancing drug on AMPA receptor currents and synaptic transmission in hippocampus. J. Pharmacol. Exp. Ther.  278: 627-638.

Arai A, Lynch G (1998) The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization.  Brain Res., 799: 230-234.

Arai A, Lynch G. (1998) AMPA receptor desensitization modulates synaptic responses induced by repetitive afferent stimulation in hippocampal slices.   Brain Res., 799: 235-242.

Arai AC, Xia Y-F, Rogers G, Lynch G, Kessler M  (2002) Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action. J. Pharmacol. Exp. Ther. 303: 1075-1085.

Johnson SA, Luu NT, Herbst TA, Knapp R, Lutz D, Arai A, Rogers GA, Lynch G (1999)  Synergistic interactions between ampakines and antipsychotic drugs.  J. Pharmacol Exp Ther 289:392-397.

Xia Y-F, Arai AC (2005) AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons. Neuroscience Aug 25. 
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Davis CM, Moskovitz B, Nguyen MA, Arai A, Lynch G, Granger R (1997) A profile of the behavioral changes produced by facilitation of AMPA-type glutamate receptors. Psychopharmacol. 133: 161-167. 

Xia Y-F, Arai AC (2005) AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons. Neuroscience Aug 25. 
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Arai AC, Xia Y-F, Suzuki E (2004) Modulation of AMPA receptor kinetics differentially influences formation of synaptic plasticity in the hippocampus. Neuroscience 123: 1011-1024. 

Arai AC, Xia Y-F, Rogers G, Lynch G, Kessler M  (2002) Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action. J. Pharmacol. Exp. Ther. 303: 1075-1085.

Lauterborn J, Lynch G, Vanderklish P, Arai A, Gall C. (2000) Modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J. Neuroscience,20: 8-21.

Xia Y-F, Arai AC (2005) AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons. Neuroscience Aug 25. 

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Hennegriff M, Arai A, Kessler M, Vanderklish P, Mutneja MS, Rogers G,  Neve RL, Lynch G (1997) Stable expression of functional AMPA type glutamate receptor subunit in human embryonic kidney cells: effects of allosteric AMPA receptor modulators on binding properties.   J. Neurochem. 68: 2424-2434.

Lauterborn J, Lynch G, Vanderklish P, Arai A, Gall C. (2000) Modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J. Neuroscience,20: 8-21.
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Phillips D, Sonnenberg J, Arai AC, Vaswani R, Krutzik PO, Kleisli T, Kessler M, Granger R, Lynch G, Chamberlin R (2002) R. 5'-Alkyl-benzothiadiazides: A new subgroup of AMPA receptor modulators with improved affinity. J. Bioorganic Medicinal Chemistry, 10: 1229-1248.
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Arai AC, Xia Y-F, Suzuki E (2004) Modulation of AMPA receptor kinetics differentially influences formation of synaptic plasticity in the hippocampus. Neuroscience 123: 1011-1024. 

Arai A, Lynch G (1996) Response to repetitive stimulation of AMPA receptors in patches excised from fields CA1 and CA3 of the hippocampus,  Brain Res. 716: 202-206.

Kessler M, Rogers G, Arai AC (2000) The norbornyl moiety of cyclothiazide determines the preference for flip-flop variants of AMPA receptor subunits.    Neurosci. Lett. 287: 161-165.

Kessler M, Arai A, Quan A, Lynch G (1996)  Effect of cyclothiazide on binding properties of AMPA-type glutamate receptors: lack of competition between cyclothiazide and GYKI 52466.  Mol. Pharmacol. 49: 123-131.

Arai A, Lynch G (1998) The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization.  Brain Res., 799: 230-234.

Arai A, Lynch G. (1998) AMPA receptor desensitization modulates synaptic responses induced by repetitive afferent stimulation in hippocampal slices.   Brain Res., 799: 235-242.

Arai AC, Kessler M, Rogers G, Lynch G  (2000) Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466.  Molecular Pharmacol. 58: 802-813.

Arai A, Kessler M, Ambros-Ingerson J, Quan A, Yigiter E, Rogers G,  Lynch G. (1996) Effects of a centrally active benzoylpyrrolidine drug on AMPA receptor kinetics.  Neuroscience, 75: 573-585.

Lin B, Brucher FA, Coligin LL, Arai AC, Lynch G. (2002) Interactions between recording technique and AMPA receptor modulators.   Brain Res., 955: 164-173.

Xia Y-F, Arai AC (2005) AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons. Neuroscience Aug 25. 
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Kessler M, Arai A, Quan A, Lynch G (1996)  Effect of cyclothiazide on binding properties of AMPA-type glutamate receptors: lack of competition between cyclothiazide and GYKI 52466.  Mol. Pharmacol. 49: 123-131.

Arai AC, Kessler M, Rogers G, Lynch G  (2000) Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: interactions with cyclothiazide and GYKI 52466.  Molecular Pharmacol. 58: 802-813.

Xia Y-F, Arai AC (2005) AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons. Neuroscience 135: 555-567. 
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Arai A, Guidotti A, Costa E, Lynch G. (1996) Effects of IDRA 21, a cognitive enhancer, on synaptic transmission and long-term potentiation in hippocampal slices, NeuroReport,  7: 2211-2215.

Arai A, Black J, Lynch G (1994)  Origins of the variations in long-term potentiation between synapses in the basal versus apical dendrites of hippocampal neurons.  Hippocampus  4:  1-10.

Arai A, Lynch G (1992)  Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation.  Brain Res. 598: 173-184.

Arai A, Lynch G (1992)  Antagonists of the platelet-activating factor receptor block long-term potentiation in hippocampal slices. Eur. J. Neurosci., 4: 411-419.

Muller D, Arai A, Lynch G (1992) Factors governing the potentiation of NMDA receptor mediated responses in hippocampus.  Hippocampus 2: 29-38.

Vanderklish P, Neve R, Bahr B, Arai A, Hennegriff M, Larson J, Lynch G (1992) Translational suppression of a glutamate receptor subunit impairs long-term potentiation,  Synapse 12: 333-337.

Kessler M, Arai A, Vanderklish P, Lynch G. (1991)  Failure to detect changes in AMPA receptor binding after long-term potentiation.  Brain Res. 560: 337-341.

del Cerro S, Arai A, Lynch G (1990) Inhibition of long-term potentiation by an antagonist of platelet activating factor receptors. Behav. Neural Biol. 54: 213-217.

Arai A, Kessler M, Lynch G (1990) The effects of adenosine on the development of long-term potentiation. Neurosci. Lett. 119: 41-44. 

Arai A, Larson J, Lynch G (1990)  Anoxia reveals a vulnerable period in the development of long-term potentiation.  Brain Res. 511: 353-357. 
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Arai A, Silberg J, Lynch G. (1995) Differences in the refractory properties of two distinct inhibitory circuitries in field CA1 of the hippocampus,  Brain Res. 704: 298-306.

Xia Y-F, Arai AC (2005) AMPA receptor modulators have different impact on hippocampal pyramidal cells and interneurons. Neuroscience Aug 25. 
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Arai AC, Kessler M (2001) Delayed neuronal damage in hippocampal slices: Long-term recording with a multielectrode dish. 31st Annual Meeting for the Society for Neuroscience Abs 95.1(Soc. Neurosci. Abstr.27: 95.1). 

Arai A, Kessler M, Lee K, Lynch G. (1990)  Calpain inhibitors improve the recovery of synaptic transmission from hypoxia in hippocampal slices. Brain Res. 532: 63-68.

Arai A, Vanderklish P, Kessler M, Lee K, Lynch G (1991)  A brief period of hypoxia causes proteolysis of cytoskeletal proteins in hippocampal slices.  Brain Res. 555: 276-280. 

Vanderklish PV, Saido TC, Gall C, Arai A, Lynch G (1995) Proteolysis of spectrin by calpain accompanies theta-burst stimulation in cultured hippocampal slices.  Mol. Brain Res. 32: 25-35.

del Cerro S, Arai A, Kessler M, Bahr B, Vanderklish P, Lynch G (1994)  Stimulation of NMDA receptor activates calpain in cultured hippocampal slices Neurosci. lett.  167: 149-152.

Lee KS, Frank S, Vanderklish P, Arai A, Lynch G (1991)  Inhibition of proteolysis protects hippocampal neurons from ischemia.  Proc. Natl. Acad. Sci. 88: 7233-7237.
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Lin SHS, Arai AC, Espana RA, Berridge CQ, Leslie F, Huguenard JR, Vergnes M, Civelli, O.  (2002) Prolactin Releasing Peptide (PrRP) promotes waking and suppresses absence seizures in rats.    Neuroscience 114: 229-238.

Xia Y-F, Kessler M, Arai AC (2002) Differential effect of AMPA receptor modulators on synaptic transmission in the thalamus and hippocampus.  32nd Annual Meeting for the Scociety for Neuroscience  Abs 540.5 (Soc. Neurosci. Abstr.28: 540.5).

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Arai AC, Xia Y-F, Suzuki E, Kessler M, Civelli O, Nothacker H-P. (2005) The cancer metastasis suppressing peptide metastin upregulates excitatory synaptic transmission in hippocampal dentate granule cells. J. Neurophysiol, 94: 3648-3652. 

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Lin SHS, Arai AC, Wang Z, Nothacker HP, Civelli O. (2001) The carboxyl terminus of the prolactin releasing peptide (PrRP) receptor interacts with PDZ domain proteins involved in AMPA receptor clustering.    Mol. Pharmacol., 60: 916-924.

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Suzuki E, Kessler M, Arai AC (2008) The fast kinetics of AMPA GluR3 receptors is selectively modulated by the TARPs gamma-4 and gamma-8. Mol Cell Neurosci. in press. 
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Wu Y, Arai AC, Rumbaugh G, Srivastava AK, Turner G, Hayashi T,  Suzuki E, Jiang Y, Zhang L, Rodriguez J, Boyle J, Tarpey P, Raymond FL, Nevelsteen J, Froyen G, Stratton M, Futreal A, Gecz J, Stevenson R, Schwartz CE, Valle D, Huganir RL, Wang T (2007) Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc. Natl. Acad. Sci. USA, 104: 18153-18168. 

Suzuki E, Kessler M, Arai AC (2005) C-terminal truncation affects kinetic properties of GluR1 receptors. Mol Cell Neurosci. 29: 1-10. 

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Kessler M, Suzuki E, Montgomery K, Arai AC.(2008) Physiological significance of high- and low-affinity agonist binding to neuronal and recombinant AMPA receptors.  Neurochem Int.

Montgomery K, Suzuki E, Kessler M, Arai AC.(2007) Factors affecting guanine nucleotide binding to rat AMPA receptors. Brain Res. 1177:1-8. Epub 2007 Aug 16.

Kessler M, Arai AC (2006) Use of [³H]fluorowillardiine to study properties of AMPA allosteric modulators. Brain Res. 1076: 25-41.

Suzuki E, Kessler M,  Montgomery K, Arai AC (2004) Divergent effects of the purinoceptor antagonists suramin and PPNDS on AMPA receptors. Mol. Pharmacol. 66:1738-1747. 

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Last modified by ACA on 04/27/2008