1. Current knowledge on the pathophysiology of schizophrenia
4/11/2017
Current knowledge on the pathophysiology
of schizophrenia
Emphasis on factors affecting emotion regulation
BIOS E 232
Sabina Berretta, MD
Harvard Medical School McLean Hospital

2. Plan for today’s class • Review Presentations:
* Eva Xia, Carlin Aloe, Teresa Morales Gerbaud
• Today’s seminar:
Current knowledge on the pathophysiology of schizophrenia
Emphasis on factors affecting emotion regulation
• Journal club presentations and discussion:
• Teresa MORALES GERBAUD
Benes, F.M., Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology, (1): p
• April GARDNER
Tamminga, C.A., A.D. Stan, and A.D. Wagner, The hippocampal formation in schizophrenia. Am J Psychiatry, (10): p

3. Current knowledge on the pathophysiology of schizophrenia

4. Strong genetic component
Supported by family, twin and adoption studies
Heritability of schizophrenia has been estimated to be between 65-80% (That is that approximately 65-80% of individual differences in schizophrenia may be attributable to genetic differences)

5. Some schizophrenia candidate genes and their association with schizophrenia according to chromosomal location, genetic association, biology/animal models, expression alterations, and meta-analysis results
Tiwari et al. 2010

6. Main domains of schizophrenia pathophysiology
Neuronal migration
• Neurodevelopment
Neuronal connectivity
Synapse formation
Extracellular matrix
Dopamine
• Neurotransmission
Glutamate
GABA
Serotonin
Synaptic proteins
• Synaptic physiology
Neurotransmitter uptake/synthesis
Extracellular matrix
• Immune system
Cytokines
Complements components

7. Structural brain abnormalities in schizophrenia:
Weinberger, NIH
• Increased ventricle size
• Brain region volume changes
Shenton et al., 1992

8. OPFC ACG DLPFC MD Striatum Amygdala ECx HP
4/11/2017
OPFC
Social behavior
Representation of reinforcer
values
ACG
Attention
Motivation
Response selection
DLPFC
Executive cognitive functions
Strategy generation
Working memory MD
Attention
Decoding of
stimulus/significance
relationship
Striatum
Reward mechanisms
Incentive salience
Amygdala
Attribution of emotional value
Fear/anxiety
Social behavior
ECx
Gating of cortical and subcortical
inputs to the HP
Memory processing HP
Context-related cognitive
processing
Episodic memory

9. Neurodevelopment Neuronal migration
Interstitial white matter neurons are increased in the superficial white matter. Their expression of NAPDH (Akbarian) and somatostatin (Yang) suggests that they are interneurons. Yang showed a significant negative correlation between SSTmRNA expression in gray matter and NeuN IWMN density.
Neuronal nuclear antigen (NeuN)–positive neurons (A) below grey matter (grey matter/white matter border represented by dotted line). In superficial white matter from (B) control and (C) schizophrenia subjects.
Yang et al., 2011

10. Historically, the main neurotransmitter systems have been a major focus in schizophrenia
• Dopamine
• GABA
• Glutamate
• Serotonin
• Acetylcholine
Guillin et al., 2007

11. Dopamine role in the pathophysiology of schizophrenia
• Rabbits treated with reserpine (which blocks neurotransmitter uptake into monoaminergic nerve terminal storage sites) display catalepsy–the maintenance of even abnormal body posture
Carlsson,
• Dopamine D2 receptors are targeted by antipsychotics and symptoms of schizophrenia are improved by dopamine antagonists
Carlsson, 1963
• Dopamine releasing agents (e.g. amphetamine) exacerbate symptoms of schizophrenia
Ellison et al., 1983

12. The strongest evidence so far is for dopamine dysregulation in the striatum
Dopamine D2 receptor availability in striatal subregions measured by PET with carbon 11–labeled raclopride before and during pharmacologically induced dopamine depletion.
In the associative striatum, acute dopamine
depletion resulted in a larger increase in D2 receptor availability in patients with schizophrenia than in control subjects suggesting
higher synaptic dopamine concentration.
In schizophrenia, increased D2 receptor transmission in pre commissural dorsal caudate (circle) might affect information processing from the dorsolateral prefrontal cortex
Kegeles et al. 2010

13. The DOPAMINE hypothesis of schizophrenia:
4/11/2017
The DOPAMINE hypothesis of schizophrenia:
Version III
• Multiple ‘‘hits’’ interact to result in dopamine dysregulation—the final common pathway to psychosis in schizophrenia.
Howes and Kapur, 2009
• The locus of dopamine dysregulation moves from being primarily at the D2 receptor
level to being at the presynaptic dopaminergic control level
• Dopamine dysregulation is linked to ‘‘psychosis’’ rather than schizophrenia
From Heinz, SZ Bull 36(3)472
DA is conceptualized as representing a prediction error that indicates the difference between received and predicted reward. In this context, DA mediates the attribution of incentive salience to conditioned cues that predict reward. Increased DA activity in the striatum of SZ may attribute INCENTIVE SALIENCE to otherwise irrelevant stimuli. This mechanisms is postulated to underlie delusion formation
• In the striatum, dopamine dysregulation is hypothesized to alter the appraisal of stimuli, perhaps through a process of aberrant salience. Increased dopamine activity in the striatum of SZ may attribute INCENTIVE SALIENCE to otherwise irrelevant stimuli. This mechanism is postulated to underlie delusion formation
• In the PFC, chronic low levels of dopamine, and compensatory increase of D1 receptors, may play a role in cognitive impairment

14. DAT-IR fiber varicosities are decreased in the LN, BN, ABN and CO in schizophrenic subjects

15. Evidence for excess DA transmission derives from pre- and postsynaptic studies. Excess DA transmission may impair glutamatergic NMDA transmission by a D2-mediated impaired presynaptic release of glutamate and an imbalance of D1/D2 opposing effects onto NMDA transmission
Guillin et al., 2007