2. 


Hideyo Noguchi, 1911: Syphillis (delusions,
grandiosity, impulsivity, altered thought
structure) is due to bacterium.
Emil Kraeplin, 1919: dementia praecox
(paranoia, grandiose delusions, auditory
hallucinations, abnormal emotional reg.,
bizarre thoughts)—partly genetic
Eugen Bleuler, 1911: key is dissociative
thinking; also delusions, hallucinations,
affective disturbance, autism.

5. 
Why does one twin become
schizophrenic and the other does not?
•
•
•
•
Lower birth weight
More physiological distress
More submissive, tearful, sensitive
Impaired motor coordination

7. 

Genes scattered across all but 8
chromosomes have been implicated
Most important:
•
•
•
•
•

Neuregulin 1: NMDA, GABA, & Ach receptors
Dysbindin: synaptic plasticity
Catechol-O-methyl transferase: DA metabol.
G72: regulates glutamatergic activity
Others: myelination, glial function
Paternal age: more cell divisions in
sperm

8. 
Larger ventricles
• Subgroup: inverse correlation between ventricle
size and response to drugs

12. 
Hippocampus, amygdala,
parahippocamp.
• Smaller in affected twin (static trait)
• Disordered hippocampal pyramidal cells
 Correlation between cell disorder and severity
 May be due to maternal influenza in 2nd trimester
• Also in entorhinal, cingulate, parahippocampal
cortex

16. 
Increased loss of gray matter in
adolescence

18. 


Shrinkage of cerebellar vermis
Thicker corpus callosum
Frontal lobes
•
•
•
•
Abnormal neuronal migration in one study
Dendrites have fewer spines
But no major structural abnormalities
Measures of frontal function impaired

19. 
Hypofrontality hypothesis
• Discordant twins: low frontal blood flow only in
affected twin
• Wisconsin card sorting task
 Schizophrenics can’t shift attn. to other criterion
 Functional imaging: frontal lobe activity lower at rest,
esp. in right hemisphere, does not increase during
task.
 Drug treatment increased activation of frontal lobes

21. 


LSD, mescaline  confusion, delirium,
disorientation, visual hallucinations.
But schizophrenic hallucinations are
mostly auditory
Schizophrenics given LSD say it’s
different from their symptoms

22. 



Amphetamine (very high doses) 
paranoia, delusions, auditory
hallucination
Also exacerbates symptoms of schiz.
Effects blocked by DA antagonist
chlorpromazine
Phenothiazines (incl. chlorprom.) & all
other typical neuroleptics block D2
receptors and alleviate (+) symptoms.

24. 



Clozapine blocks 5-HT2A receptors > D2
As effective as typical neuroleptics on (+)
symptoms, more effective on (-)
symptoms
Fewer motor side effects (tardive
dyskinesia)
Actually increase DA release in frontal
cortex
• L-DOPA can even be beneficial

26. 

Problem with DA hypothesis: time course
Phencyclidine (PCP): dissociative
anesthetic 
• Auditory hallucinations
• Depersonalization
• Delusions
• Noncompetitive NMDA antagonist (blocks Ca2+
channel)

29. 
2 weeks PCP in monkeys  schiz.-like
symptoms
• Including poor performance on frontal lobe-
sensitive task



Dose- & time-sensitive
Ketamine (NMDA antag) similar effects
So, why not give glutamate agonists to
treat schizophrenia?????

30. 
Seizures!! (also excitotoxicity)

Try mGluR agonists: 8 subtypes of mGluR
• Some modulate glutamate release
• Others modulate dopamine systems