Neuronal Mechanisms in Schizophrenia

Robert Freedman, M.D.

Department of Psychiatry

University of Colorado

Denver, Colorado

“He saw the world in a way no one could have imagined.”

Schizophrenia

• 1% affected, onset generally late adolescence to early adulthood

• Auditory hallucinations and paranoid delusions are the most common forms of thought disorder, the most characteristic chronic symptom

• A decrement in psychosocial function, often called “negative symptoms” is part of the illness

Sensory Gating Disturbance

• “My mind has to be here, it has to be there, it has to be everywhere. I can’t concentrate on anything.”

• “When he gets ill, his sense of hearing seems to increase. He hears the neighbors across street arguing.”

The decrease of nicotinic receptors on nerve cells means that the brain’s own acetylcholine is no longer sufficient to

activate the neurons that filter out noises

fMRI indicates increased hemodynamic activity in the hippocampus in schizophrenia during smooth pursuit eye movements

…even though uninterested and autistically encapsulated patients pay little attention to the outside world, they register a remarkable number of events of no concern to them. The selection which attention exercises over normal sensory impressions may be reduced to zero, so that almost everything that meets the senses is registered. Thus both the facilitating and inhibitory propensities of attention are disordered. Bleuler, 1911

Grandfather—Chronically Insane

Father—Committed Suicide

Proband--- Philosopher Arthur Schopenhauer

“The amount of noise which anyone can bear undisturbed stands in inverse proportion to his mental capacity….Noise is a torture to all intellectual people.”

3’UTR

Human 7 Gene Structure

Promoter

1 2 3 5 6 7 8 94 10

1 2 3 4 5 6 7 8 9

Introns

Exons

2602 bp

-2600 +2

1062 bp

-1076 -15

231 bp

-245 -15

A.

B.

The decrease of nicotinic receptors on nerve cells means that the brain’s own acetylcholine is no longer sufficient to

activate the neurons that filter out noises

A. Control female, -86 C/C

T/C= 0.14

B. Control female, -86 C/T

T/C= 0.60

Conditioning Testing

P50

C. Schizophrenic female, -86 C/T

T/C= 0.54

50 ms

4V

1-Dopamine adjusts the volume

2-Acetycholine and GABA filter signal from noise

3-Glutamate imprints new memories

Acetycholine and GABA filter signal from noise

Dopamine increases the volume

Glutamate imprints new memories.

1-Dopamine adjusts the volume—Blocked by antipsychotic

2-Acetycholine and GABA filter signal from noise

3-Glutamate imprints new memories

Nicotine mimics the brain chemical acetylcholine, (but it also poisons acetylcholine receptors!)

First Degree RelativeNicotine can temporarily restore nerve cell inhibition

Decreased hippocampal activity during eye movement in schizophrenics after

nicotine treatment

Clozapine, a drug used to treat schizophrenia, increases acetylcholine and normalizesinhibition; cigarette smoking drops by 50%

The University of Colorado with NARSAD, Stanley, and NIMH and VA support, is developing new drugs to treat schizophrenia and bipolar disorder by targeting nicotinic

receptors.

1-Dopamine adjusts the volume

2-Acetycholine and GABA filter signal from noise

3-Glutamate imprints new memories

Memory disorder in schizophrenia• Decreased ability to learn efficiently• Poverty of content• Persistence of paranoid memory

• Malfunction of NMDA and other glutamate receptors

• Decreased volume of brain regions critical to cognition

• Diminished extinction

Veterans without PTSD have enhanced cingulateresponse to combat stimuli—Shin et al., 2001

Genetics, Neurobiology, and Our Conception of Schizophrenia

• Schizophrenia used to be conceptualized as a rare, disastrous malfunction of the mind and/or brain, depending on your view of Cartesian dualism

• If three independent factors are involved, then an application of Mendel’s second law suggests that for a population prevalence of schizophrenia = 0.01, the prevalence of any one of these factors is 0.011/3 = 0.22. Calculate the probability that you have at least one factor. What might its effect be on your mental function?

Then came "a miraculous remission." And as happens, for reasons unknown,in the case of some people with schizophrenia,it was not, according to Mrs. Nash, due to any drug or treatment:"It's just a question of living a quiet life."