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Animal Models of Gain Control in Schizophrenia Steven J. Siegel, M.D., Ph.D.

Translational Neuroscience Program. Steven J. Siegel, M.D., Ph.D. Animal Models of Gain Control in Schizophrenia Steven J. Siegel, M.D., Ph.D. Director, Tranlational Neuroscience Program siegels@upenn.edu CNTRICS - 7/31/2014. Translational Neuroscience Program.

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Animal Models of Gain Control in Schizophrenia Steven J. Siegel, M.D., Ph.D.

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  1. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Animal Models of Gain Control in Schizophrenia Steven J. Siegel, M.D., Ph.D. Director, Tranlational Neuroscience Program siegels@upenn.edu CNTRICS - 7/31/2014

  2. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Scope & framework for modeling gain control • EEG - clinically relevant & foster preclincal translation • Sensory systems - provide stimulus / input control • Evaluate neural response a stimulus - i.e. can assess gain • Rodent equivalents to human measures • Disease models - Schizophrenia • Pharmacological, endocrine, genetic • Treatment models • Examples of medication effects • Limitations: • Averages vs. single trial analysis

  3. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Scope & framework for modeling gain control • EEG - clinically relevant & foster preclincal translation • Sensory systems - provide stimulus / input control • Evaluate neural response a stimulus - i.e. can assess gain • Rodent equivalents to human measures • Disease models - Schizophrenia • Pharmacological, endocrine, genetic • Treatment models • Examples of medication effects • Limitations: • Averages vs. single trial analysis

  4. Translational Neuroscience Program S1 S2 S1 S2 Steven J. Siegel, M.D., Ph.D. Auditory Event Related Potentials • EEG responses to sensory stimuli - evaluate the I/O function • Mouse & human analogy for response properties & pharmacology

  5. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Relevance to Schizophrenia • Original phenotype in unmedicated schizophrenia was reduced S1 response amplitude - i.e. reduced gain (Adler, L.E. et. al., Biol Psych., 1986, Freedman, R., et. al. Biol. Psych. 1983; Jin, Y. et.al., Psych. Research 1997) • Schizophrenia patients noted to have smaller visual ERP amplitude and less increase in amplitude with increasing stimulus intensity - i.e. reduced gain (Landau, S, et. al. Arch Gen Psych 1975) Control Schizophrenia

  6. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Rodent equivalents for human measures Generation of human componentsP50: Auditory thalamus and STGN100: STG & other placesP200: Association auditory cortexPicton et al., Electroencephalogr Clin Neurophysiol.1974Human component qualitiesP50 Increases amplitude 0.25-1 secAdler, L.E., et. al.N100 Gating 0.5s, ISI 0.25-8 sec & Intensity dependenceBoutros, N., et. al. Psychiatry Res, 1999, Javitt, D., et. al. Clin Neurophys, 2000P200 Intensity dependenceHegerl, U., et. al. Psychiatry Res, 1992 Umbricht et. al, Brain Research 2004

  7. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. P2 P1 N1 Mouse latency is 40% of that in humans

  8. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Scope & framework for modeling gain control • EEG - clinically relevant & foster preclincal translation • Sensory systems - provide stimulus / input control • Evaluate neural response a stimulus - i.e. can assess gain • Validation of rodent equivalents to human measures • Disease models - Schizophrenia • Pharmacological, endocrine, genetic • Treatment models • Examples of medication effects • Limitations: • Averages vs. single trial analysis

  9. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. • Disease Models • Ketamine - NMDA R antagonists • Corticosterone - stress • Gas transgenic mice • Amphetamine

  10. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Consider N1 and MMN as examples of gain control Active Attentional Shifts Pre-attentive Sensory Perception MMN Human 0 100 200 300 400 500 MSEC Mouse 0 40 80 120 160 200 MSEC Task-Dependent Activity: Salience detection Working Memory Stimulus Evaluation Stimulus Cortical Activation

  11. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Ketamine causes lasting reduction of initial response - i.e. Gain Pattern similar for N40 & P80 at 3 & 5 weeks post treatment Sal Ket Sal Ket S1 S2

  12. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Ketamine effects on deviance ERPs

  13. Translational Neuroscience Program Control Ketamine Steven J. Siegel, M.D., Ph.D. Ketamine Disrupts Deviance ERPs - MMN

  14. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. High dose Corticosterone used to model stress-induced alterations in symptoms: Reduces S1 amplitude - i.e. Gain

  15. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Corticosterone alters gain, not gating

  16. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Gas mice show many endophenotypes of schizophrenia including deficits in spatial & associative learning as well as PPI • ABR • No differences in threshold - similar to schizophrenia (Pfefferbaum, 1980) • Wt & Tg differ in stimulus intensity response (p = 0.02) - i.e. gain • N40 • Tg have smaller N40 amplitude than Wt - similar to schizophrenia • Tg have reduced N40 intensity function

  17. Translational Neuroscience Program Haloperidol Amphetamine Steven J. Siegel, M.D., Ph.D. • Haloperidol eliminates Tg intensity function deficit • Amphetamine approximates Tg intensity function deficit • Reverse translational question - Do patients differ on ABR and N100 intensity function?

  18. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Scope & framework for modeling gain control • EEG - clinically relevant & foster preclincal translation • Sensory systems - provide stimulus / input control • Evaluate neural response a stimulus - i.e. can assess gain • Validation of rodent equivalents to human measures • Disease models - Schizophrenia • Pharmacological, endocrine, genetic • Treatment models • Examples of medication effects • Limitations: • Averages vs. single trial analysis

  19. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. • Treatment & Translational Models • Antipsychotics • Haloperidol & Olanzapine increase amplitude • Drug-target evaluation using gain models - PDE4 inhibitors • Nicotine & nicotinic agonists alter S1 amplitude • Translational validity with varenicline

  20. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Olanzapine & haloperidol increase amplitude at long ISI no effects at short ISI - i.e. antipsychotics increase the gain of the system leading to an apparent change in gating * *

  21. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Nicotine & Varenicline increase S1 amplitude of Human - P50 *

  22. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Nicotine & Varenicline increase S1 amplitude of Mouse - P20 *

  23. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Translational model of gain control Rolipram acts like an antipsychotic to increase S1 response

  24. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Scope & framework for modeling gain control • EEG - clinically relevant & foster preclincal translation • Sensory systems - provide stimulus / input control • Evaluate neural response a stimulus - i.e. can assess gain • Validation of rodent equivalents to human measures • Disease models - Schizophrenia • Pharmacological, endocrine, genetic • Treatment models • Examples of medication effects • Limitations: • Averages vs. single trial analysis

  25. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Several potential mechanisms to explain changes in amplitude on an averaged response Latency jitter hypothesis - low ITC Amplitude hypothesis - low signal Low amplitude Low amplitude

  26. Saline Saline Haloperidol Amphetamine Translational Neuroscience Program Previous studies suggest increased latency jitter in schizophrenia Mouse amphetamine & haloperidol models suggest changes in single trial amplitude as well 180 ms 700 ms Steven J. Siegel, M.D., Ph.D.

  27. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Reduction of gamma ITC in Schizophrenia previously shown by Roach and MathalonSchizophr Bull.2008; 34: 907-926 wavelet decomposition Auditory Evoked Potential Phase-Locking Plot Penn subjects display reduced gamma PLF in schizophrenia n = 20/group (p < 0.04), consistent with previous findings

  28. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. NR1 hypomorphic Mice have deficits in Gamma ITC • 12% normal expression of NMDA R1 • social, self care, learning & memory impairments • Reduction of PV interneurons related to generation of gamma oscillations • However, ERP amplitudes are larger in NR1 hypomorphs - suggesting that gain and ITC are not entirely synonymous

  29. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Summary • Schizophrenia patients display a reduced relationship between stimulus intensity and response intensity for ERPs - i.e. reduced gain. • ERP data are often expressed as an average of multiple trials to a single stimulus, obscuring effects of latency jitter versus gain in single trials • May be helpful to evaluate intensity functions and single trial data for S1 responses in schizophrenia. • Animal models can assess the potential determinants of reduced and increased gain control using highly translatable EEG and ERP methods

  30. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Thank You

  31. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Ketamine disrupts deviance ERPs * * ** **

  32. Translational Neuroscience Program Trial1 2 3 Phase 4 Steven J. Siegel, M.D., Ph.D. Gamma Activity & Intertrial Coherence • Disrupted in schizophrenia & autism • Rhythmic activity in 30 – 100 Hz range • Local coupling of neuronal assemblies • Mechanism: synchronization of pyramidal cells by fast-spiking interneurons • Cognitive correlates, e.g. working memory • ITC - measure of EEG synchronization with an external stimulus at a particular frequency = consistency of response Stimulus Evoked Response

  33. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Use models for therapeutic development:GABA Rescue of Gamma Deficits * p < 0.02; ** p < 0.004 • Baclofen, selective GABAB agonist: rescues gamma PLF deficits in NR1neo-/-mice

  34. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Use models for therapeutic development:GABA Rescue of Gamma Deficits * p < 0.02 • Clordiazepoxide, non-selective GABAA positive modulator: reduces gamma PLF in both groups

  35. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Bupropion - indirect monoamine agonist & nicotinic antagonist Primary effects are on amplitude - only see the effects of nicotine on gating with illness plus treatment in the model

  36. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. • Normal mouse • Mouse on chronic bupropion • Mouse on bupropion + haloperidol • Mouse on bupropion + haloperidol + nicotine

  37. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Medicated schizophrenia patients have abnormalities in gamma & theta oscillations

  38. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Supplemental Summary • Intertrial coherence influences amplitude if ERPs, similar to latency jitter, but is not the only factor involved. • Gating abnormalities may represent a mixed phenotype that results from a combination of reduced gain from the illness and effects of medication.

  39. Translational Neuroscience Program Steven J. Siegel, M.D., Ph.D. Previous Staff: Mary Dankert Farzin Irani Christina Maxwell Kayla Metzger Patrick Connolly Breanne Weightman Wendy Zhang Debbie Ikeda Jake Burnbaum. Chalon Majewski-Tiedeken. Noam Rudnick Richard Ehrlichman Laura Amann Brianna Weightman Staff: Yuling Liang, MD Post-Docs Robert Featherstone, PhD Valerie Tatard, Ph.D. Graduate Students Mike Gandal Robert Lin John Saunders Hiren Makadia Undergraduate Students Tony Thieu Stefanie Fazio Dheepa Sekar Eric chu Sarah Doherty Mili Mehta Yufei Cao Previous Post Docs: Jenny Phillips, Ph.D. Tobias Halene, M.D., Ph.D. Previous Students: Jonathan Kahn Danielle Trief Sonalee Majumdar Michelle Mergenthal Jennifer Fleisher Jonathan Abelson Jack Kent Danit Mayor Karen Rudo Josh Stillman Julia Glasser William Beckerman Neal Ghandi Rachel Klein Suzanne Wilson Omid Motobar Cara Rabin Jon Talmud Steve Luminaise Julie Sisti Christina Bodarky Randal Toy Viral Gandhi Karen Ryall Jing-Yuan Ma Joe Crisanti Stephen McKenna Amar Bains Xavier Readus Lillia Rodriguez Jimmy Suh Jennifer Croner Rachel Rosenberg James Wang Mia Wang Marcella Chung Kimia Pourrezai Victoria Behrend Philip Santoiemma Collaborators Basic: Steve Arnold, Konrad Talbot Chang-Gyu Hahn, Greg Carlson Ted Abel, Diego Contreras Julie Blendy, Ted Brodkin Lief Finkel, M. Lazarewicz Clinical: Raquel Gur, Ruben Gur, Bruce Turetsky - Neuropsychiatry Caryn Lerman, Andrew Strasser TTURC Tim Roberts & Chris Edger, CAR/CHOP • NIMH, NIDA, NCI • Commonwealth of PA • SMRI, NARSAD • NuPathe, AstraZeneca, Lilly • ITMAT, Abramson Cancer Center

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