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

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Current knowledge on the pathophysiology of schizophrenia

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Current knowledge on the pathophysiology

of schizophrenia

Emphasis on factors affecting emotion regulation

BIOS E 232

Sabina Berretta, MD

Harvard Medical School McLean Hospital

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:


Benes, F.M., Amygdalocortical circuitry in schizophrenia: from circuits to molecules.Neuropsychopharmacology, 2010. 35(1): p. 239-57


Tamminga, C.A., A.D. Stan, and A.D. Wagner, The hippocampal formation in schizophrenia. Am J Psychiatry, 2010. 167(10): p. 1178-93

Current knowledge on the pathophysiology of schizophrenia

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)

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

Main domains of schizophrenia pathophysiology

Neuronal migration

Neuronal connectivity

• Neurodevelopment

Synapse formation

Extracellular matrix



• Neurotransmission



Synaptic proteins

• Synaptic physiology

Neurotransmitter uptake/synthesis

Extracellular matrix


• Immune system

Complements components

Structural brain abnormalities in schizophrenia:

• Increased ventricle size

• Brain region volume changes

Weinberger, NIH

Shenton et al., 1992


Social behavior

Representation of reinforcer





Response selection


Executive cognitive functions

Strategy generation

Working memory



Decoding of




Reward mechanisms

Incentive salience


Attribution of emotional value


Social behavior


Gating of cortical and subcortical

inputs to the HP

Memory processing


Context-related cognitive


Episodic memory




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

Historically, the main neurotransmitter systems have been a major focus in schizophrenia

• Dopamine


• Glutamate

• Serotonin

• Acetylcholine

Guillin et al., 2007

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, 1957-1959

• 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

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

The DOPAMINE hypothesis of schizophrenia:

Version III

• Multiple ‘‘hits’’ interact to result in dopamine dysregulation—the final common pathway to psychosis in schizophrenia.

• 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

Howes and Kapur, 2009

• 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


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

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

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