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

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, 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 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 • 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

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

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

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

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

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: 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

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