Research Group


Research Interests

We list here some of the major active projects ongoing in our laboratories, along with some of the people in our groups working on the projects. Click on each project to learn more, including publications and a brief description.

Some of our group's recent publications are listed below.

 

Persistent adaptive presynaptic plasticity

We have been studying a lasting but reversible form of presynaptic plasticity at glutamate synapses. We find that presynaptic terminals adapt to long-term or severe changes in overall activity with binary changes in the priming status of glutamatergic vesicles. Increases in activity and strong activation of Gi/o-linked G protein coupled receptors promote decreased glutamate release; decreases in neuronal activity promote increased release. Surprisingly the adaptation is largely binary. Increases in activity block exocytosis of vesicles from entire presynaptic terminals in response to both calcium-dependent and calcium-independent secretagogues. Our evidence suggests degradation of priming proteins Rim1 and/or munc13 may participate in silencing, and recent work implicates astrocytes in the maturation of presynaptic silencing.

 

Neurosteroids

We are collaborating with Doug Covey’s lab in the Department of Molecular Biology & Pharmacology and with Joe Henry Steinbach, Gustav Akk, and Alex Evers in the Anesthesiology Department to understand regulation of GABA and glutamate receptors by neurosteroids. Neurosteroids are synthesized within the CNS and have direct actions on ligand-gated ion channels, notably GABA-A receptor and NMDA receptors. We have been particularly interested in GABA receptor modulation because these receptors are likely modulated by endogenous levels of neurosteroids.

Recent work has focused on understanding the importance of membrane partitioning in the access of neurosteroids to the GABA-A receptor. For this work we have used fluorescently tagged neurosteroid analogs to follow steroid movement into and out of neurons. An unexpected recent finding was that these tagged steroids are sometimes inert until excited with appropriate wavelengths of light, at which time they become active at GABA receptors. Other recent work has focused on understanding other novel neuromodulators, particularly those acting at NMDA-type glutamate receptors.

Recent work with neurosteroids and other modulators have recently led to the establishment of the Taylor Family Institute for Innovative Psychiatric Research, centered on discovery of novel pharmacological strategies for treating psychiatric disease.

 

Fast biosensors of dopamine release

“Slow” transmitters like dopamine are critically important to reward, attention, and neuropsychiatric disease. However, unlike fast neurotransmitters (e.g., glutamate), whose ligand-gated ion channels give us a faithful, linear readout of release of the cognate neurotransmitter, dopamine GPCRs do not give a faithful readout of the timing, plasticity, and modulation of dopamine release. Presynaptic imaging and electrochemistry are partial but ultimately unsatisfying solutions to the issue. We have set about making fast dopamine synapses by heterologously introducing a ligand-gated dopamine receptor with properties that make it a good synaptic biosensor for dopamine. With this approach we hope to study the modulation of dopamine release with resolution not heretofore possible.

 

Collaborations

Budding collaborations with other WU investigators include study of GPCR regulation, the study of tonic vs. phasic GABA signaling, and the study of the physiological properties of neurons re-programmed from patient skin samples. We are also collaborating with Dr. Larry Eisenman (WU Neurology) to develop tools for analysis of connectivity in small neural networks. Other collaborations include studies with Dr. Bruce Carlson to study sensory processing in weakly electric fish using single-axon recording techniques, and Dr. Andrew Yoo to characterize excitability of newly converted neurons from human fibroblasts.

 
Recent Publications
  1. Fast phasic release properties of dopamine studied with a channel biosensor.

    Kress GJ, Shu HJ, Yu A, Taylor A, Benz A, Harmon S, Mennerick S.

    J Neurosci. 2014 Aug 27

  2. Acute and chronic effects of ethanol on learning-related synaptic plasticity.

    Zorumski CF, Mennerick S, Izumi Y.

    Alcohol. 2014 Feb.

  3. Indistinguishable synaptic pharmacodynamics of the N-methyl-D-aspartate receptor channel blockers memantine and ketamine.

    Emnett CM, Eisenman LN, Taylor AM, Izumi Y, Zorumski CF, Mennerick S.

    Mol Pharmacol. 2013

  4. Non-competitive, Voltage-dependent NMDA Receptor Antagonism by Hydrophobic Anions.

    Linsenbardt A, Chisari M, Yu A, Shu HJ, Zorumski CF,Mennerick SJ.

    Mol Pharmacol. 2012 Nov 9.

  5. Astrocyte-derived thrombospondins mediate the development of hippocampal presynaptic plasticity in vitro.

    Crawford DC, Jiang X, Taylor A, Mennerick S.

    J Neurosci.2012 Sep 19;32(38):13100-10.

  6. Synaptic NMDA receptors mediate hypoxic excitotoxic death.

    Wroge CM, Hogins J, Eisenman L, Mennerick S.

    J Neurosci. 2012 May 9;32(19):6732-42.

  7. Cross talk between synaptic receptors mediates NMDA-induced suppression of inhibition.

    Chisari M, Zorumski CF, Mennerick S.

    J Neurophysiol. 2012 May;107(9):2532-40.

  8. Excitotoxicity triggered by Neurobasal culture medium.

    Hogins J, Crawford DC, Zorumski CF, Mennerick S.

    PLoS One. 2011;6(9):e25633.

  9. Characteristics of concatemeric GABA(A) receptors containing α4/δ subunits expressed in Xenopus oocytes.

    Shu HJ, Bracamontes J, Taylor A, Wu K, Eaton MM, Akk G, Manion B, Evers AS, Krishnan K, Covey DF, Zorumski CF, Steinbach JH, Mennerick S.

    Br J Pharmacol. 2012 Apr;165(7):2228-43. 

  10. Presynaptically silent synapses: dormancy and awakening of presynaptic vesicle release.

    Crawford DC, Mennerick S.

    Neuroscientist. 2012 Jun;18(3):216-23. 

  11. Presynaptic silencing is an endogenous neuroprotectant during excitotoxic insults.

    Hogins J, Crawford DC, Jiang X, Mennerick S.

    Neurobiol Dis. 2011 Aug;43(2):516-25.

  12. Hydrophobic anions potently and uncompetitively antagonize GABA(A) receptor function in the absence of a conventional binding site.

    Chisari M, Wu K, Zorumski CF, Mennerick S.

    Br J Pharmacol. 2011 Sep;164(2b):667-80.

  13. Calcium-independent inhibitory G-protein signaling induces persistent presynaptic muting of hippocampal synapses.

    Crawford DC, Chang CY, Hyrc KL, Mennerick S.

    J Neurosci. 2011 Jan 19;31(3):979-91.


 
 


 

 


 
   
Washington University in St. Louis
Department of Psychiatry