Physiology and Pharmacology

Elizabeth I. Tietz, Ph.D.

Professor Emerita

Telephone:
(419) 383-4182, 383-4170

FAX:
(419) 383-2871


e-mail
Liz.Tietz@utoledo.edu

Training

  • B.S., Psychology, 1976, University of Illinois, Champaign, IL
  • M.A., Clinical Psychology, 1978, Xavier University, Cincinnati, OH
  • Ph.D., Biopsychology and the Neuroscience Program, 1983, Wayne State University, Detroit, MI

Appointments

  • Postdoctoral Research Fellow in Neuropharmacology, Department of Pharmacology, Medical University of Ohio, 1983-1985
  • Instructor of Pharmacology and Therapeutics, Medical College of Ohio, 1984-1985
  • Assistant Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1985-1991
  • Visiting Associate Professor of Neurology, University of Michigan College of Medicine, 1994-1995
  • Associate Professor of Pharmacology and Therapeutics, Medical College of Ohio, 1992-1998
  • Director, Cellular and Molecular Neurobiology Graduate Program, Medical College of Ohio, Health Science Campus, 2003-2007
  • Director, Neurosciences and Neurological Disorders Track, Biomedical Sciences Graduate Program, 2007-2008
  • Director, Toledo RISE in North American Program, German Academic Exchange Service, DAAD, 2009-present
  • Director ASPET Zannoni SURF Program, 2010-2012
  • Professor of Physiology and Pharmacology, University of Toledo College of Medicine (formerly Medical College of Ohio; Medical University of Ohio), Health Science Campus, 1998-present
  • Vice-Chair, Department of Physiology and Pharmacology, University of Toledo College of Medicine, Health Science Campus, 2006-2011
  • Professor, Department of Neurosciences, Joint Appointment, University of Toledo College of Medicine, Health Science Campus, 2010-present
  • Professor Emerita, Department of Physiology and Pharmacology, and Department of Neurosciences, University of Toledo College of Medicine, Health Science Campus, 2012-present

Research Interests

Our NIDA funded research program has focused on the synaptic mechanisms of benzodiazepine (BZ) tolerance and physical dependence, forms of use-dependent synaptic plasticity. Chronic treatment of rats with BZs, positive allosteric modulators of GABA-A receptor (GABAR) function, results in a reduction of their anticonvulsant effectiveness which significantly limits their clinical usefulness and the appearance of withdrawal symptoms leading to BZ misuse and abuse. Using extracellular, intracellular and whole-cell approaches we have developed an in vitro hippocampal slice model to investigate the functional bases for BZ tolerance development and more recently BZ physical dependence which result in a altered signal transduction at inhibitory and excitatory hippocampal CA1 synapses, respectively.

Our electrophysiological studies related to BZ tolerance have shown that chronic BZ treatment has time-dependent effects to alter BZ and GABAR agonist potency and has profound effects on hippocampal GABAR-mediated inhibition in CA1 pyramidal cells. Additional molecular and immunohistochemical approaches have suggested structural changes in the GABAR. Specifically, the time-dependent regulation of specific alpha1- and beta3-containing GABAR subtypes may contribute to impaired GABA inhibition in CA1 pyramidal cells. These findings were lent support by functional studies of in vitro CA1 neuron tolerance to the alpha1 selective drug, zolpidem. A transient upregulation of alpha4 and alpha5 subunits was also detected. The rapid time-course of the effect of flumazenil, a BZ antagonist, to reverse both functional and structural correlates of BZ tolerance suggests that translational and post-translational mechanisms may each play interdependent roles in mediating BZ tolerance.

More recent cell-attached single channel analyses suggest that GABA suggest a marked reduction in channel opening frequency at low GABA concentrations in CA1 neuron patches from flurazepam-withdrawn rats compared to controls, consistent with a reduction in GABA affinity. These findings may to some extent explain the “silent” GABAergic synapses detected in this in vivo model. More recently we have shown that delayed reduction in GABAR function following BZ withdrawal might be related to activation of phosphorylation / dephosphorylation by increased intracellular Ca2+, consistent with the doubling of voltage-gated calcium channel current density described below.

Our functional and structural studies of excitatory amino acid receptor (EAAR) systems in this model suggest that bi-directional modulation of AMPA and NMDAR receptors in hippocampal CA1 neurons, contributes to expression/masking of anxiety-like behavior and thus contribute to BZ physical dependence. AMPA receptor (AMPAR)-mediated miniature (m)EPSC amplitude are increased in hippocampal CA1 neurons from 1-day (15-30%) and 2-day (30-50%) FZP-withdrawn rats, while NMDA receptor (NMDAR) currents were depressed by 50% in 2-day FZP withdrawn rats [8,9]. There was a significant positive correlation between the potentiation of AMPAR current amplitude and anxiety-like behavior measured in the elevated plus-maze in 1-day withdrawn rats, but anxiety was not observed 2-days after cessation of treatment. Preinjection of the AMPA antagonist 24 hours prior to behavioral testing and/or electrophysiological recording blocked potentiation of AMPAR currents and the appearance of anxiety. On the contrary, latent anxiety-like behavior was unmasked in 2-day FZP-withdrawn rats by systemic injection of the NMDA antagonist, which prevented the reduction in NMDAR, but not AMPAR currents. Collectively, these findings provide strong support for the hypothesis that BZ physical dependence, manifested as anxiety-like behavior, is related to the modulation of hippocampal glutamatergic neurotransmission, and the depression of NMDAR currents may serve as a natural break to alleviate anxiety.

Electrophysiological and immunohistochemical studies indicated that increased AMPAR-mediated neurotransmission was related to an increase in Ca2+-permeable GluR1 homomers reflected in a negative shift in rectification in the presence of spermine analogues and an increase in glutamate efficacy Confocal immunocytochemical studies and postembedding immunogold electron microscopic studies confirmed an increase in GluR1, but not GluR2 subunits at CA1 neuron asymmetric synapses. Findings to-date suggest that CA1 neuron AMPAR potentiation during BZ withdrawal involves a two-step process, GluR1 homomer incorporation followed by CaMKII-mediated Ser831GluR1 phosphorylation. CaMKII-mediated phosphorylation of GluR1 subunits may serve as a common final pathway for promoting both activity-dependent plasticity and drug-induced adaptations at CA1 pyramidal neuron synapses associated with BZ physical dependence.

Initial findings indicate a decrease in ifenprodil-sensitive NR2B-mediated currents along with a decrease in NR1 and NR2B, but not NR2A subunits at CA1 synapses of 2-day FZP-withdrawn rats is responsible for the depression of NMDA function. However, unlike with models of activity-dependent plasticity such as LTP, L-VGCCs, rather than NMDARs may be responsible for initiating Ca2+-mediated signaling mechanisms associated with AMPAR potentiation since, prior injection with the L-type voltage-gated (L-VGCC) antagonist, nimodipine, also prevented AMPAR potentiation and anxiety, (as well as changes in GABA-A receptor dysfunction) consistent with a doubling of high voltage-activated calcium channel current density in CA1 neurons immediately and up to 2-days after FZP withdrawal.

We are currently evaluating the role of multiple sources of Ca2+ entry in the regulation of inhibitory and excitatory synapses associated with chronic drug treatment and withdrawal. 


Representative Publications  

Last Updated: 6/26/15