current knowledge on the pathophysiology of schizophrenia
Post on 24-Feb-2016
31 Views
Preview:
DESCRIPTION
TRANSCRIPT
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
top related