Translational Neuroscience Program
Animal Models of
Gain Control
in Schizophrenia
Steven J. Siegel, M.D., Ph.D.
Director, Tranlational Neuroscience Program
siegels@upenn.edu
CNTRICS - 3/14/2016
1
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Scope & framework for modeling gain control
•
EEG - clinically relevant & foster preclincal translation
–
–
–
•
Disease models - Schizophrenia
–
•
Sensory systems - provide stimulus / input control
Evaluate neural response a stimulus - i.e. can assess gain
Rodent equivalents to human measures
Pharmacological, endocrine, genetic
Treatment models
– Examples of medication effects
•
Limitations:
–
Averages vs. single trial analysis
2
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Scope & framework for modeling gain control
•
EEG - clinically relevant & foster preclincal translation
–
–
–
•
Disease models - Schizophrenia
–
•
Sensory systems - provide stimulus / input control
Evaluate neural response a stimulus - i.e. can assess gain
Rodent equivalents to human measures
Pharmacological, endocrine, genetic
Treatment models
– Examples of medication effects
•
Limitations:
–
Averages vs. single trial analysis
3
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Auditory Event Related Potentials
• EEG responses to sensory stimuli - evaluate the I/O function
• Mouse & human analogy for response properties & pharmacology
S1
S2
S1
S2
4
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Rodent equivalents for human measures
Generation of human components
P50:
Auditory thalamus and STG
N100:
STG & other places
P200:
Association auditory cortex
Picton et al.,
Electroencephalogr Clin Neurophysiol. 1974
Human component qualities
P50
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, 2000
P200
Intensity dependence
Hegerl, U., et. al. Psychiatry Res, 1992
Umbricht et. al, Brain Research 2004
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
8
Human and Mouse overlay of Evoked Responses
225
mouse
human
150
4
P2
P1
75
mV
0
0
-4
-75
-150
-8
0
50
100
N1
150
200
250
Time
300
350
Mouse latency is 40% of that in humans
400
450
500
7
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Scope & framework for modeling gain control
•
EEG - clinically relevant & foster preclincal translation
–
–
–
•
Disease models - Schizophrenia
–
•
Sensory systems - provide stimulus / input control
Evaluate neural response a stimulus - i.e. can assess gain
Validation of rodent equivalents to human measures
Pharmacological, endocrine, genetic
Treatment models
– Examples of medication effects
•
Limitations:
–
Averages vs. single trial analysis
8
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Disease Models
•Ketamine - NMDA R antagonists
•Corticosterone - stress
•Gas transgenic mice
•Amphetamine
9
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Consider N1 and MMN as examples of gain control
Active Attentional
Shifts
Pre-attentive
Sensory
Perception
Human 0
Mouse 0
100
40
200
80
300
120
400
160
500
200
MSEC
MSEC
MMN
Stimulus
Evaluation
Stimulus
Cortical
Activation
Task-Dependent
Activity:
Salience detection
Working Memory
10
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Ketamine effects on deviance ERPs
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Ketamine Disrupts Deviance ERPs - MMN
Control
Ketamine
13
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
High dose Corticosterone used to model stress-induced
alterations in symptoms: Reduces S1 amplitude - i.e. Gain
14
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Corticosterone alters gain, not gating
8.0 seconds
0.25 seconds
15
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Haloperidol
Amphetamine
• Haloperidol eliminates Tg intensity function deficit
• Amphetamine approximates Tg intensity function deficit
• Reverse translational question - Do patients differ on ABR
and N100 intensity function?
17
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Scope & framework for modeling gain control
•
EEG - clinically relevant & foster preclincal translation
–
–
–
•
Disease models - Schizophrenia
–
•
Sensory systems - provide stimulus / input control
Evaluate neural response a stimulus - i.e. can assess gain
Validation of rodent equivalents to human measures
Pharmacological, endocrine, genetic
Treatment models
– Examples of medication effects
•
Limitations:
–
Averages vs. single trial analysis
18
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
*
*
20
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
4
Nicotine & Varenicline increase S1 amplitude of
Human - P50
3
mV
*
2
1
0
Placebo Abstinent
Placebo Smoking
Varenicline
Abstinent
Varenicline
Smoking 21
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
100
mV
75
Nicotine & Varenicline increase S1 amplitude of
Mouse - P20
*
50
25
0
Saline
Nicotine
Varenicline
Nicotine
Varenicline22
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Translational model of gain control
Rolipram acts like an antipsychotic to increase S1 response
23
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Scope & framework for modeling gain control
•
EEG - clinically relevant & foster preclincal translation
–
–
–
•
Disease models - Schizophrenia
–
•
Sensory systems - provide stimulus / input control
Evaluate neural response a stimulus - i.e. can assess gain
Validation of rodent equivalents to human measures
Pharmacological, endocrine, genetic
Treatment models
– Examples of medication effects
•
Limitations:
–
Averages vs. single trial analysis
24
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Several potential mechanisms to explain
changes in amplitude on an averaged response
4
4
Latency jitter hypothesis - low ITC
Amplitude hypothesis - low signal
0
0
-4
-4
-8
-8
-12
-12
-16
-16
0
5
10
15
20
25
30
0
4
4
0
0
-4
-4
-8
-8
5
Low amplitude
10
15
20
25
20
25
Low amplitude
-12
-12
-16
-16
0
5
10
15
20
25
0
5
10
15
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Previous studies suggest increased latency jitter in schizophrenia
Mouse amphetamine & haloperidol models suggest changes in single trial
amplitude as well
Saline
Saline
180 ms
Amphetamine
700 ms
Haloperidol
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Reduction of gamma ITC in Schizophrenia
previously shown by Roach and Mathalon Schizophr Bull.2008; 34: 907-926
wavelet
decomposition
Auditory Evoked Potential
C
S
6
Phase-Locking Plot
-50
0
50
100
150
-50
0
50
100
150
-50
0
50
100
150
-50
0
50
100
150
Potential (mV)
4
2
0
-2
-4
-6
-400
-200
Time (ms)
0
200
400
600
Penn subjects display reduced gamma PLF in schizophrenia n =
20/group (p < 0.04), consistent with previous findings
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
NR1 Hypomorphs
Wild Type
150
100
50
0
-50
-100
-150
-200
0
0.05
0.1
0.15
0.2
0.25
0.3
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
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EEG and ERP methods
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Thank You
30
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Ketamine disrupts deviance ERPs
*
*
** **
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
Trial
1
2
3
4
-50
0
50
100
150
-50
0
50
100
150
-50
0
50
100
150
100
150
Phas
e
-50
0
50
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Use models for therapeutic development:
GABA Rescue of Gamma Deficits
0.60
0.50
0.40
0.30
Baseline
Baclofen
**
*
*
0.20
0.10
0.00
NR1neo -/-
WT
* p < 0.02; ** p < 0.004
• Baclofen, selective GABAB agonist: rescues gamma PLF deficits in
NR1neo-/-mice
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Use models for therapeutic development:
GABA Rescue of Gamma Deficits
Average 30-80 Hz ITC
0.60
0.50
Baseline
Chlordiazepoxide
0.40
*
0.30
*
0.20
0.10
0.00
NR1neo -/-
WT
* p < 0.02
• Clordiazepoxide, non-selective GABAA positive modulator: reduces
gamma PLF in both groups
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
35
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
•
Normal mouse
•
Mouse on chronic bupropion
•
Mouse on bupropion + haloperidol
•
Mouse on bupropion + haloperidol +
nicotine
36
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
Medicated schizophrenia patients have abnormalities
in gamma & theta oscillations
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Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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.
38
Steven J. Siegel, M.D., Ph.D.
Translational Neuroscience Program
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
•
•
•
•
•
NIMH, NIDA, NCI
Commonwealth of PA
SMRI, NARSAD
NuPathe, AstraZeneca, Lilly
ITMAT, Abramson Cancer Center
Previous Post Docs:
Previous Staff:
Mary Dankert
Jenny Phillips, Ph.D.
Farzin Irani
Tobias Halene, M.D., Ph.D.
Christina Maxwell
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
Kayla Metzger
Patrick Connolly
Breanne Weightman
Wendy Zhang
Debbie Ikeda
Jake Burnbaum.
Chalon Majewski-Tiedeken.
Noam Rudnick
Richard Ehrlichman
Laura Amann
Brianna Weightman
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
39
Steven J. Siegel, M.D., Ph.D.