Animal Models of

1

• Animal Models of
• Gain Control
• in Schizophrenia
• Steven J. Siegel, M.D., Ph.D.
• Director, Tranlational Neuroscience Program
• siegels_at_upenn.edu
• CNTRICS - 8/7/2015

2
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
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

• Auditory Event Related Potentials
• EEG responses to sensory stimuli - evaluate the
  I/O function
• Mouse human analogy for response properties
  pharmacology

5
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
Generation of human componentsP50 Auditory
thalamus and STGN100 STG other
placesP200 Association auditory cortex
Picton et al., Electroencephalogr Clin
Neurophysiol. 1974Human component
qualitiesP50 Increases amplitude 0.25-1
sec Adler, L.E., et. al.N100 Gating 0.5s, ISI
0.25-8 sec Intensity dependence Boutros, N.,
et. al. Psychiatry Res, 1999, Javitt, D., et.
al. Clin Neurophys, 2000P200 Intensity
dependence Hegerl, U., et. al. Psychiatry Res,
1992
Rodent equivalents for human measures
Umbricht et. al, Brain Research 2004
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P2
P1
N1
Mouse latency is 40 of that in humans
8
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

• Disease Models
• Ketamine - NMDA R antagonists
• Corticosterone - stress
• Gas transgenic mice
• Amphetamine

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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
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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
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Ketamine effects on deviance ERPs
13
Ketamine Disrupts Deviance ERPs - MMN
14
High dose Corticosterone used to model
stress-induced alterations in symptoms Reduces
S1 amplitude - i.e. Gain
15
Corticosterone alters gain, not gating
16
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

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• 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
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

• 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
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
Nicotine Varenicline increase S1 amplitude of
Human - P50

22
Nicotine Varenicline increase S1 amplitude of
Mouse - P20

23
Translational model of gain control Rolipram acts
like an antipsychotic to increase S1 response
24
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
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
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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
Reduction of gamma ITC in Schizophrenia
previously shown by Roach and Mathalon Schizophr
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 lt 0.04), consistent
with previous findings
28
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

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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

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Thank You
31
Ketamine disrupts deviance ERPs




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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
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Use models for therapeutic developmentGABA
Rescue of Gamma Deficits
p lt 0.02 p lt 0.004

• Baclofen, selective GABAB agonist rescues gamma
  PLF deficits in NR1neo-/-mice

34
Use models for therapeutic developmentGABA
Rescue of Gamma Deficits
p lt 0.02

• Clordiazepoxide, non-selective GABAA positive
  modulator reduces gamma PLF in both groups

35
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

• Normal mouse
• Mouse on chronic bupropion
• Mouse on bupropion haloperidol
• Mouse on bupropion haloperidol nicotine

37

• Medicated schizophrenia patients have
  abnormalities in gamma theta oscillations

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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

• 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

Previous Staff Mary Dankert Farzin
Irani Christina Maxwell Kayla Metzger Patrick
Connolly Breanne Weightman Wendy Zhang Debbie
Ikeda Jake Burnbaum. Chalon Majewski-Tiedeken. No
am 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
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