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

schizophreniaEmphasis on factors affecting emotion regulation

• Journal club presentations and discussion:• Teresa MORALES GERBAUDBenes, F.M., Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology, 2010. 35(1): p. 239-57• April GARDNER 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 componentSupported by family, twin and adoption studiesHeritability 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)

Tiwari et al. 2010

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

Main domains of schizophrenia

pathophysiology• Neurodevelopment

• Neurotransmission

• Synaptic physiology

Neuronal migrationNeuronal connectivitySynapse formation

DopamineGlutamateGABASerotonin

Extracellular matrix

Synaptic proteinsNeurotransmitter uptake/synthesisExtracellular matrix

• Immune system CytokinesComplements components

Structural brain abnormalities in schizophrenia:

• Increased ventricle size

Weinberger, NIH• Brain region volume changes

Shenton et al., 1992

AmygdalaAttribution of emotional value

Fear/anxietySocial behavior

OPFCSocial behavior

Representation of reinforcer values

ACGAttention

MotivationResponse selection

DLPFCExecutive cognitive functions

Strategy generationWorking memory

ECxGating of cortical and subcortical

inputs to the HPMemory processing

HPContext-related cognitive

processingEpisodic memory

MDAttention

Decoding of stimulus/significance

relationship

StriatumReward mechanisms

Incentive salience

NeurodevelopmentNeuronal migration

Yang et al., 2011

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.

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.

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

• Dopamine

• GABA

• 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

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 dopaminedepletion resulted in a larger increase in D2 receptor availability in patients with schizophrenia than in control subjects suggestinghigher synaptic dopamine concentration.

In schizophrenia, increased D2 receptor transmission in pre commissural dorsal caudate (circle) might affect information processing from the dorsolateral prefrontal cortexKegeles et al. 2010

The strongest evidence so far is for dopamine dysregulation in the striatum

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 receptorlevel to being at the presynaptic dopaminergic control level• Dopamine dysregulation is linked to ‘‘psychosis’’ rather than schizophrenia

• 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

Howes and Kapur, 2009

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

subjectsLN

Guillin et al., 2007

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