animal models of gain control in schizophrenia steven j. siegel, m.d., ph.d

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Animal Models of Animal Models of Gain ControlGain Control

in Schizophreniain Schizophrenia

Steven J. Siegel, M.D., Ph.D.Steven J. Siegel, M.D., Ph.D.Director, Tranlational Neuroscience ProgramDirector, Tranlational Neuroscience Program

[email protected]@upenn.edu

CNTRICS - CNTRICS - 04/22/2304/22/23

Steven J. Siegel, M.D., Ph.D.Steven J. Siegel, M.D., Ph.D.

Translational Neuroscience ProgramTranslational Neuroscience Program

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• EEG - clinically relevant & foster preclincal translationEEG - clinically relevant & foster preclincal translation– Sensory systems - provide stimulus / input control Sensory systems - provide stimulus / input control – Evaluate neural response a stimulus - i.e. can assess gainEvaluate neural response a stimulus - i.e. can assess gain– Rodent equivalents to human measuresRodent equivalents to human measures

• Disease models - SchizophreniaDisease models - Schizophrenia– Pharmacological, endocrine, geneticPharmacological, endocrine, genetic

• Treatment modelsTreatment models– Examples of medication effectsExamples of medication effects

• Limitations:Limitations:– Averages vs. single trial analysisAverages vs. single trial analysis



Scope & framework for modeling gain controlScope & framework for modeling gain control

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• EEG - clinically relevant & foster preclincal translationEEG - clinically relevant & foster preclincal translation– Sensory systems - provide stimulus / input control Sensory systems - provide stimulus / input control – Evaluate neural response a stimulus - i.e. can assess gainEvaluate neural response a stimulus - i.e. can assess gain– Rodent equivalents to human measuresRodent equivalents to human measures







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Auditory Event Related PotentialsAuditory Event Related Potentials• EEG responses to sensory stimuli - evaluate the I/O functionEEG responses to sensory stimuli - evaluate the I/O function

• Mouse & human analogy for response properties & pharmacologyMouse & human analogy for response properties & pharmacology



S1 S2S1S2

5Steven J. Siegel, M.D., Ph.D.Steven J. Siegel, M.D., Ph.D.


ControlControl Schizophrenia Schizophrenia

• Original phenotype Original phenotype in unmedicated schizophrenia was reduced reduced S1 response amplitude 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)

Relevance to SchizophreniaRelevance to Schizophrenia

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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 secAdler, 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 dependenceHegerl, U., et. al. Psychiatry Res, 1992



Rodent equivalents for human measuresRodent equivalents for human measures

Umbricht et. al, Brain Research 2004

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Human and Mouse overlay of Evoked Responses

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0 50 100 150 200 250 300 350 400 450 500Time

mV

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mousehuman



P1

N1

P2

Mouse latency is 40% of that in humans Mouse latency is 40% of that in humans

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• EEG - clinically relevant & foster preclincal translationEEG - clinically relevant & foster preclincal translation– Sensory systems - provide stimulus / input control Sensory systems - provide stimulus / input control – Evaluate neural response a stimulus - i.e. can assess gainEvaluate neural response a stimulus - i.e. can assess gain– Validation of rodent equivalents to human measuresValidation of rodent equivalents to human measures







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Disease ModelsDisease Models

•Ketamine - NMDA R antagonistsKetamine - NMDA R antagonists

•Corticosterone - stressCorticosterone - stress

•GGs transgenic mices transgenic mice

•AmphetamineAmphetamine



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Human 0 100 200 300 400 500 MSEC

Pre-attentive

CorticalActivation

StimulusEvaluation

Active AttentionalShifts

Task-Dependent Activity:

Salience detectionWorking Memory

SensoryPerception

StimulusStimulus

Mouse 0 40 80 120 160 200 MSEC

MMN



Consider N1 and MMN as examples of gain controlConsider N1 and MMN as examples of gain control

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Ketamine causes lasting reduction of initial response - i.e. GainKetamine causes lasting reduction of initial response - i.e. GainPattern similar for N40 & P80 at 3 & 5 weeks post treatmentPattern similar for N40 & P80 at 3 & 5 weeks post treatment



S1 S2

Sal

Sal

Ket

Ket

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Ketamine effects on deviance ERPs



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Ketamine Disrupts Deviance ERPs - MMNKetamine Disrupts Deviance ERPs - MMN



ControlControl KetamineKetamine



High dose Corticosterone used to model stress-induced High dose Corticosterone used to model stress-induced alterations in symptoms: Reduces S1 amplitude - i.e. Gainalterations in symptoms: Reduces S1 amplitude - i.e. Gain

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8.0 seconds

0.25 seconds



Corticosterone alters gain, not gatingCorticosterone alters gain, not gating



GGs mice show many endophenotypes of schizophrenia s mice show many endophenotypes of schizophrenia including deficits in spatial & associative learning as well as PPI including deficits in spatial & associative learning as well as PPI

• ABRABR• No differences in threshold - similar to schizophrenia No differences in threshold - similar to schizophrenia (Pfefferbaum, 1980)(Pfefferbaum, 1980)

• Wt & Tg differ in stimulus intensity response (p = 0.02) - i.e. gainWt & Tg differ in stimulus intensity response (p = 0.02) - i.e. gain

• N40N40

• Tg have smaller N40 amplitude than Wt - similar to schizophreniaTg have smaller N40 amplitude than Wt - similar to schizophrenia

• Tg have reduced N40 intensity functionTg have reduced N40 intensity function

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• Haloperidol eliminates Tg intensity function deficitHaloperidol eliminates Tg intensity function deficit

• Amphetamine approximates Tg intensity function deficitAmphetamine approximates Tg intensity function deficit

• Reverse translational question - Do patients differ on ABR Reverse translational question - Do patients differ on ABR and N100 intensity function? and N100 intensity function?



Haloperidol Amphetamine

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Treatment & Translational ModelsTreatment & Translational Models

• Antipsychotics Antipsychotics

• Haloperidol & Olanzapine increase amplitudeHaloperidol & Olanzapine increase amplitude

• Drug-target evaluation using gain models - Drug-target evaluation using gain models - PDE4 inhibitorsPDE4 inhibitors

• Nicotine & nicotinic agonists alter S1 amplitudeNicotine & nicotinic agonists alter S1 amplitude

• Translational validity with vareniclineTranslational validity with varenicline





Olanzapine & haloperidol increase amplitude at long ISI Olanzapine & haloperidol increase amplitude at long ISI

no effects at short ISI - i.e. antipsychotics increase the gain no effects at short ISI - i.e. antipsychotics increase the gain of the system leading to an apparent change in gatingof the system leading to an apparent change in gating

**

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0

1

2

3

4

Placebo Abstinent Placebo Smoking VareniclineAbstinent

VareniclineSmoking

mV

*

Nicotine & Varenicline increase S1 amplitude of Nicotine & Varenicline increase S1 amplitude of Human - Human - P50P50



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0

25

50

75

100

Saline Nicotine Varenicline NicotineVarenicline

m V

Nicotine & Varenicline increase S1 amplitude of Nicotine & Varenicline increase S1 amplitude of Mouse - Mouse - P20P20

*



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Translational model of gain controlTranslational model of gain controlRolipram acts like an antipsychotic to increase S1 responseRolipram acts like an antipsychotic to increase S1 response



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Latency jitter hypothesis - low ITCLatency jitter hypothesis - low ITC Amplitude hypothesis - low signalAmplitude hypothesis - low signal

Several potential mechanisms to explain Several potential mechanisms to explain changes in amplitude on an averaged responsechanges in amplitude on an averaged response

Low amplitudeLow amplitude Low amplitudeLow amplitude

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Amphetamine

Saline

Haloperidol

Saline


Previous studies suggest increased latency jitter in schizophreniaPrevious studies suggest increased latency jitter in schizophreniaMouse amphetamine & haloperidol models suggest changes in single trial Mouse amphetamine & haloperidol models suggest changes in single trial

amplitude as wellamplitude as well


180 ms 700 ms

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Reduction of gamma ITC in Schizophrenia Reduction of gamma ITC in Schizophrenia previously shown by previously shown by Roach and Mathalon Schizophr Bull.2008; 34: 907-926

-400 -200 0 200 400 600

-6

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Time (ms)

Pot

entia

l (m V

)

CS

Auditory Evoked Potential Phase-Locking Plotwavelet

decomposition

Penn subjects display reduced gamma PLF in schizophrenia n = 20/group (p < 0.04), consistent with previous findings



-50 0 50 100 150

-50 0 50 100 150

-50 0 50 100 150

-50 0 50 100 150

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NR1 hypomorphic Mice NR1 hypomorphic Mice have deficits in Gamma ITChave 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

-200

-150

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NR1 HypomorphsWild Type

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SummarySummary• Schizophrenia patients display a reduced relationship Schizophrenia patients display a reduced relationship

between stimulus intensity and response intensity for ERPs between stimulus intensity and response intensity for ERPs - i.e. reduced gain.- i.e. reduced gain.

• ERP data are often expressed as an average of multiple ERP data are often expressed as an average of multiple trials to a single stimulus, obscuring effects of latency jitter trials to a single stimulus, obscuring effects of latency jitter versus gain in single trialsversus gain in single trials

• May be helpful to evaluate intensity functions and single May be helpful to evaluate intensity functions and single trial data for S1 responses in schizophrenia.trial data for S1 responses in schizophrenia.

• Animal models can assess the potential determinants of Animal models can assess the potential determinants of reduced and increased gain control using highly translatable reduced and increased gain control using highly translatable EEG and ERP methodsEEG and ERP methods





Thank YouThank You

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Ketamine disrupts deviance ERPs

**

** **



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Gamma Activity & Intertrial Coherence

• Disrupted in schizophrenia & autismDisrupted in schizophrenia & autism• Rhythmic activity in 30 – 100 Hz rangeRhythmic activity in 30 – 100 Hz range

– Local coupling of neuronal assembliesLocal coupling of neuronal assemblies• Mechanism: synchronization of pyramidal Mechanism: synchronization of pyramidal

cells by fast-spiking interneuronscells by fast-spiking interneurons• Cognitive correlates, e.g. working Cognitive correlates, e.g. working

memorymemory• ITC - measure of EEG synchronization

with an external stimulus at a particular frequency = consistency of response

Stimulus Evoked Response

-50 0 50 100 150

-50 0 50 100 150

-50 0 50 100 150

-50 0 50 100 150

2

Trial1

3

4Phase



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0.00

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NR1neo -/- WT

BaselineBaclofen

**

**

Use models for therapeutic development:Use models for therapeutic development:GABA Rescue of Gamma DeficitsGABA Rescue of Gamma Deficits

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

* p < 0.02; ** p < 0.004



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0.00

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NR1neo -/- WT

Ave

rage

30-

80 H

z IT

C

BaselineChlordiazepoxide

**

Use models for therapeutic development:Use models for therapeutic development:GABA Rescue of Gamma DeficitsGABA Rescue of Gamma Deficits

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

* p < 0.02





Bupropion - indirect monoamine agonist & nicotinic antagonist Bupropion - indirect monoamine agonist & nicotinic antagonist Primary effects are on amplitude - only see the effects of Primary effects are on amplitude - only see the effects of

nicotine on gating with illness nicotine on gating with illness plusplus treatment in the model treatment in the model

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• Normal mouseNormal mouse

• Mouse on chronic bupropionMouse on chronic bupropion

• Mouse on bupropion + haloperidolMouse on bupropion + haloperidol

• Mouse on bupropion + haloperidol + Mouse on bupropion + haloperidol + nicotinenicotine



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Medicated schizophrenia patients have abnormalities Medicated schizophrenia patients have abnormalities in gamma & theta oscillations in gamma & theta oscillations



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Supplemental SummarySupplemental Summary• Intertrial coherence influences amplitude if ERPs, similar Intertrial coherence influences amplitude if ERPs, similar

to latency jitter, but is not the only factor involved.to latency jitter, but is not the only factor involved.

• Gating abnormalities may represent a mixed phenotype that Gating abnormalities may represent a mixed phenotype that results from a combination of reduced gain from the illness results from a combination of reduced gain from the illness and effects of medication.and effects of medication.



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animal models of gain control in schizophrenia steven j. siegel, m.d., ph.d

Documents

human measuresumbricht

stimulus input control

neural response

s1 response amplitude

modeling gain controleeg

reduced gain landau

reduced gain adler

increasing stimulus