Module 3 - Schizophrenia

Question 1

What is the definition for psychosis?

Answer 1

‘Psychotic’ simply indicates the presence of hallucinations, delusions, or a limited number of severe abnormalities of behaviour, such as gross excitement and overactivity, marked psychomotor retardation, and catatonic behaviour.’ - ‘loss of contact with reality’

Question 2

What are the symptom domains of schizophrenia?

Answer 2

Positive syndrome: delusions, hallucinations
Negative syndrome (1/2-3/4s chronic schz exhibit some negative symptoms), persistent, primary negative symptoms in 15% first-episode illness, <32% established schz): Affective flattening (core), alogia (core), avolition, anhedonia, asociality
Disorganisation: formal thought disorder (also positive symptoms), thought blocking, thought insertion, withdrawal, broadcasting
Neurocognitive function (significant in 75%, stable over stages of illness, difficulty maintaining work and social connections, living independently, acquiring skills in rehab programmes, possibly stronger connection to functional outcome than psychotic symptoms): attention (sustained, selective), memory (verbal, working), executive function (ability to set goals, make decisions, coordinate activities, respone inhibition and shifting of attentional set)
Dysphoria/depressive features:
suicidality (12x more than general population, 5% patients complete suicide Carlborg 2010, highest in early stage of illness, especially after a psychotic episode), hopelessness
Impaired social cognition:
Emotion processing, Theory of Mind, social relationship perception
Disturbed behaviour: social withdrawal, thought disturbance, anti-social behaviour, depressed behaviour
Abnormal affect, eg. blunted affect or inappropriate/incongruous affect, eg. laughing at bad news (affective response is incompatible with ideas/thoughts)

Question 3

What are the classical schizophrenia subtypes?

Answer 3

Paranoid (persecutory/grandiose delusions derogatory auditory hallucinations)
Hebephrenic (disorganisation syndrome with formal thought disorder, affective flattening/incongruity, bizarre behaviour)
Catatonic (multiple motor, volitional and behavioural disorders, stupor and excitement)
Simple (insidious but progressive impoverishment of mental life, without development of florid symptoms)

Question 4

What is Crow’s model of schizophrenia and Liddle’s three syndromes?

Answer 4

Crow:
Type 1 has positive symptoms, is acute, responds well to medication, is reversible and has absent intellectual impairment. Likely to have increased DA receptors.
Type 2 has negative symptoms, is chronic and poorly responds to medication. It is therefore irreversible and intellectual impairment is present, probably because of cell loss and structural damage.

Liddle:
Psychomotor poverty (poverty of speech, decreased spontaneous movement, unchanging facial expression, paucity of expressive gesture, affective nonresponse, lack of vocal inflections)
Disorganisation syndrome (inappropriate affect, poverty of content of speech, tangentiality, derailment, circumstantiality, neologisms, word salad, pressure of speech, distractibility)
Reality distortion (voices speak to patient, delusions of persecution, delusions of reference) Liddle and Barnes 1990

Question 5

What is the life expectancy of a person with schizophrenia?

Answer 5

Reduced by 20% and is widening (Laursen 2014)
60% of excess mortality from physical illness, esp. coronary heart disease, suicide and injury, cancer
This is because patients with SMI are under-diagnosed, under-treated, inadequate care, disparities in access to health care, diagnostic shadowing, unhealthy lifestyle, physical inactivity, smoking, poor diet, poor compliance with medical treatment, risks associated with schizophrenia, eg. diabetes (Rouillon 2005) and adverse effects of antipsychotic treatment.

Question 6

What is the epidemiology of schizophrenia?

Answer 6

16-35 years, often present after 1-2 years, 1.4:1 male:female Castle 1998

Question 7

What is the genetics behind schizophrenia?

Answer 7

Monozygotic twins (48%), 46% chance of schizophrenia if both parents and 10% if siblings. The risk variants now identified are common — they contribute in most, if not all, cases.
Lots of linkage analysis: susceptibility genes across all but 8 chromosomes. Mostly SNPs, CNVs are very rare but have big effect size.
Neuregulin 1 (NMDA, GABA, ACh receptors), dysbindin (synaptic plasticity), DISC1
Association with variation in MHC (McGuffin 1979 as well), common complement C4 alleles (patients often have greater expression of protein C4A) and controls synaptic pruning by marking synapses for destruction by microglia, so excessive pruning could lead to schizophrenia (Sekar 2016)
Advancing paternal age (especially increases do novo mutations (Sipos 2004)

Linkage analysis and candidate genes haven’t been very successful - lots of genes and chromosomes and not much replication.
B2, CACNA1I - voltage gated calcium channel subunits.
Exome sequencing:
de novo: Fromer 2014: Enrichment of mutations in genes in ARC, NMDAR and FMRP pathways
GWAS between 2007-2014 - >100 genome-wide significant loci. Finally found an associated with DRD2.
Also GRM3, GRIN2A, SRR, GRIA1 in glutamergic transmission and synaptic plasticity.
Also CACNA1C, CACNtations in genes in ARC, NMDAR and FMRP pathways
de novo: Purcell 2014: Enrichment of mutations in genes in ARC, NMDAR FMRP and calcium signaling pathways again
Estimate that 8,300 independent, mostly common SNPs contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability
GWAS: Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014 found associations with B-lymphocytes, separate to MHC association.
HRNA5-A3-B4 gene cluster are strongly associated with heavy smoking13. Smoking is extremely common (more than 80% prevalence) in people with schizophrenia14, and the consortium’s identification of an associated variant in the CHRNA5-A3-B4 gene cluster might reflect a dose–response relationship between heaviness of smoking and schizophrenia risk.
Rare: DISC1 - various forms of mental illness
22q11: Velo-cardio-facial syndrome - hypoparathyroidism, Underdeveloped thymus or absent thymus, which results in problems in the immune system, heart defects, cleft lip and/or palate
Up to 1/3 VCFS patients may develop schizophrenia or other psychiatric illness
Approximately 1% of patients with schizophrenia have 22qDS.
The schizophrenia in 22qDS is indistinguishable by symptoms, treatment response, neurocognitive profile, or MRI brain anomalies.
1q21.1, 15q13.1 both 0.02%, also seen in epilepsy, autism, other non CNS.

Awadala 2010: Some of the mutations were in known disease genes such as SHANK3, IL1RAPL1 (the interleukin-1 receptor accessory protein-like 1 gene) and NRXN1 (the neurexin 1 gene)

Question 8

Discuss the effect of cannabis use on psychosis:

Answer 8

Farrell 2013 on UK prison inmates: cannabis before 16yo 2x risk functional psychosis.
Andreasson 1987: heavy use at 18yo 6-fold increase risk schizophrenia (independent of other substance use)
Dunedin (Arsenault 2002), Christchurch (Fergusson 2005) - Cannabis use increased psychotic symptoms. Henquet 2004: cannabis use moderately increases risk psychotic symptoms but stronger in those predisposed.
Moore 2007: OR = 1.4, 40% increase risk psychosis in individuals who had ever used cannabis. Dose-response effect, OR = 2.09 if used cannabis more frequently.
BUT: reverse causality? Susceptibility?
Estrada 2011: The earlier the cannabis use, the sooner the first psychiatric admission, might be because val allele of COMT Val158Met polymorphism.

Question 9

Discuss the role of DA in schizophrenia?

Answer 9

Reduced DA activity in prefrontal cortex (Block 2002) coupled with increased mesolimbic DA transmission (Voruganti 2001).

Question 10

What are some prodromal symptoms of schizophrenia?

Answer 10

Dysphoria, suspicious, perceptual distortions, poor concentration, sleep disturbance. deterioration in role function, paranoid notions, social and emotional withdrawal, academic decline, lack of drive, ritualistic behaviour, etc.

Question 11

What effects does the duration of untreated psychosis have on the disease?

Answer 11

Median time is 1-2 years (Barnes 2000), but if longer than treatment response, remission, positive symptoms and social functioning can be affected up to 8 years later. It is also linked to risk of harm to self and others (Marshall 2005)

Question 12

At what stage does depression present in schizophrenia?

Answer 12

Prodromal (50%)
As part of the acute episode (often “revealed” after positive symptoms respond to medication)
Early post-psychotic depression (resolve more slowly than other symptoms) (25%)
Last post-psychotic depression (>6 months after acute episode) (<33%) SSRI 1st-line
In other stages mentioned previously, give anti-psychotics.

Question 13

What factors increase the risk of suicide?

Answer 13

Young, male, highly educated, fear of mental disintegration, number prior suicide attempts, depressive symptoms, active hallucinations and delusions, insight, agitation/restlessness/akathisa, co-morbid PTSD, FHx suicide, comorbid subtance misuse.
Less likely if adhere to effective treatment.

Question 14

What is the definition of a hallucination?

Answer 14

Perception in the absence of an external sensory stimulus. <80% auditory, eg. voices that discuss the patient in first person, running commentary, thought echo, command hallucinations, music, body noises, machinery, can be inside head or specific external location
15% visual, especially glowing orbs or flashes of colour
5% tactile, such as feelings of being touched, sexual intercourse, pain
Olfactory and gustatory are rare

Question 15

What is the definition of a delusion?

Answer 15

A false, unshakeable belief which is out of keeping with the patient’s cultural and educational background.
Not necessarily true… could be true belief, it’s just that the justification for the belief is not logical.
Symbolic misinterpretation accompanied by strong sense of conviction. 50% patients.
Delusional mood: strange, uncanny mood in which environment appears to be changed in a threatening way that is not understood.
Commonly, delusional themes = grandiose, paranoid (being harmed or persecuted by particular person or group. May interfere with cooperating with evaluation or treatment), nihilistic (uncommon, bizarre belief that one is dead or body is breaking down or one doesn’t exist), erotomanic (believes special relationship with someone)

Question 16

Discuss insight in schizophrenia:

Answer 16

Varies - can acknowledge MI, or treatment without MI, awareness of consequences of disorder.
If good insight then more likely to adhere to medication, outpatient treatment, fewer hospital admissions but increased hopelessness, depression and suicidal behaviour.
Those with poor insight have poor treatment outcome, response to rehabilitation and medication compliance. Also unaware of social consequences of disorder associated with poor interpersonal function and social function.

Question 17

What spontaneous motor phenomena appear without medication?

Answer 17

Oral and peri-oral movements resembling normal facial expressions
Choreiform movements (Reiter)
Incoordination
Tremor
Focal and generalised epileptiform phenomena (Bleuler)

Question 18

What is the prognosis in schizophrenia?

Answer 18

<50% fairly satisfactory outcome from clinical and psychosocial point of view, with consistent number of achieving full recovery Lambert 2010
WHO International Study of Schizophrenia 16% early unremitting cases achieved late phase recovery.

Question 19

Discuss the efficacy of antipsychotic drugs:

Answer 19

Leucht 2012: in same range as medical pharmacotherapeutics.

Antipsychotic maintenance treatment reduces relapse rates from 57-22% within 10 months.

Question 20

What are the DA pathways?

Answer 20

Nigrostriatal: Substantia nigra to caudate and putamen.
Mesolimbic: ventral tegmental area in midbrain to limbic regions, inluding ventral striatum (nucleus accumbens), amygdala, hippocampus, medial prefrontal cortex.
Mesocortical: VTA to frontal cortex including dorsolateral prefrontal cortex.
Tuberoinfundibular: tuberal region to median eminence for prolactin release.

Question 21

What evidence is there for the DA theory of schizophrenia?

Answer 21

Psychostimulant agents, eg. amphetamine and cocaine trigger release of DA and are associated with de novo pschosis (Harris 2000), and worsening of psychotic symptoms in patients with partial remission (Wolkin 1994)
L-DOPA aggravates the symptoms and PD patients get hallucinations on L-DOPA.
SPECT imaging reveals enhanced amphetamine-induced release of DA compared to controls.
Postmortem and imaging studies show heightened synthesis of DA in people with schizophrenia when psychotic Seeman 2000
BUT cognitive and negative symptoms are from insufficient DA in prefrontal cortex? Slifstein 2015 Maybe because Val158Met COMT polymorphism.
Antipsychotics clinical efficacy correlates with receptor affinity at D2 receptor. >65% D2 receptor occupancy is threshold for antipsychotic efficacy but >78% for extrapyramidal side effects, including akathisia Seeman 2001
BUT maybe drugs induce state neurological suppression.
Also, why poor negative symptom control?

Question 22

What is motivational salience and what hypothesis is associated with it?

Answer 22

DA has role in reward and reinforcement so increases in DA in ventral midbrain linked to motivational salience of environmental stimuli, ie. reward-associated stimuli become focus of goal-directed behaviour. Kapur 2005 hypothesised that abnormal assignment of salience to stimuli and internal representations lead to delusions to explain aberrant salient experience and this can have impacts on behaviour or cause distress. Antipsychotics block DA an therefore dampen salience (but perhaps dampen motivational salience of normal events too?) and then the decrease in salience allows for symptoms resolution by extinction and unlearning.

Question 23

Discuss the differences and similarities between first generation antipsychotics and second generation antipsychotics:

Answer 23

Change in clinical symptoms biggest in first 2 weeks than any other 2 weeks, or first month than any other month of first year Agid 2006
Early response indicator of continued responsiveness over at least 6 months.
FGAs typically associated with prominent movement and endocrine effects, SGAs linked to metabolic and cardiovascular complications CATIE, CUtLASS, EUFEST
CAFE study: olanzapine, quetiapin, risperidone in early first episode of psychosis - mostly similarities in PANSS but differences in side effects. People less likely to discontinue with olanzapine but still fairly likely, especially as young patients more sensitive to substantial weight gain (>1/2 weight gain in 1st 12 weeks). 13% population treatment-emergent metabolic syndrome over 1 year FU
BUT CATIE trial is by Lieberman as well and CAFE is funded by Astra Zeneca. Astra Zeneca makes quetiapine which Lieberman said was not good in the CATIE trial and then he said was good in the CAFE study (after lowering the doses of olanzapine and risperidone which can actually be at slightly higher doses and not give extrapyramidal signs Kapur 2001 which is the opposite to what Lieberman said and did. Therefore SOME antipsychotics have similar efficacy but be wary of SEs.

Question 24

Discuss the rates of relapse in schizophrenia:

Answer 24

Evidence from FU studies that repeated psychotic episodes and prolonged periods of relapse may:
Impair prognosis
Lead to reduced responsiveness to antipsychotics
Worsen social function
Leads to emergence of treatment refractoriness in about 1 in 6 patients, whether first or subsequent relapse - WHO 15 year follow up study Wiersma 1998
Leucht Cochrane 2012 - 1 year relapse, 64% discontinuation medication, 27% continuation
Zipursky 2014 - FEP: 1 year relapse, 77% discontinuation, 3% with continuation (some non-randomised trials), 20% patients with FEP won’t require long term antipsychotic treatment?

MESIFOS study - FEP, dose reduction/discontinuation or maintenance treatment - 21% successfully discontinued but 30% had to re-start due to relapse, 43% in DR compared to 21% in MT (benign relapses) but twice as many with regular jobs in DR (27%) than MT. Similar symptom remission in both (68%) but functional remission DR 46%, MT 20%.
NICE guidelines recommend pharmacological relapse prevention for every patient diagnosed with schizophrenia for 1-2 years based on studies <3 years.

Wade 2006 - more relapses if comorbid substance use. Hunt 2002 - noncompliant no substance abuse relapse rates similar to compliant substance abuse.

Leucht 2012 - statistically significant association between longer study duration and smaller relapse reduction - efficacy loss over time? Poorer adherence over time?

Question 25

Discuss the adherence rates in schizophrenics:

Answer 25

Patient factors
Poor medication adherence
Comorbid substance use
Poor insight into illness
Severe residual symptoms after treatment
Male gender
Younger than 40 yrs of age
FEP:
Carers’ criticism
Poorer premorbid adjustment
Treatment factors
Poor adherence to medication Ascher-Svanum et al 2006
Poor aftercare planning before discharge from inpatient care
Poor follow-through with aftercare
Poor interaction between the patient, family members, and carers
Csernansky & Schuchart, 2002, Conley et al 2003
Predicting which patients will be rehospitalisation by clinical estimates or models often no better than chance
Atakan et al 1990, Olfson et al 1999

Non-adherence to oral antipsychotics: 40-60% Haynes 2008
25% depot preparations Young 1999
50% in FEP in 1st year medication Coldham 2002
Depots and injections:
Advantages
Avoid covert non-adherence: guaranteed delivery
Regular scrutiny of mental state and side effects
Opportunity for the health care professional administering the injection
Simplification of medication regimen: less likely to forget dose and cannot inadvertently overdose
Clarifies poor adherence v poor response/treatment refractoriness
More predictable and stable serum drug levels
Disadvantages
Slow dose titration and longer time required to achieve steady state
Increase the risk of excess dosage: particularly oral AP added
Pain/discomfort at injection site

More patients survive with depot fluphenazine (Hogarty 1979), relapse differences vary a lot between investigators in 70s-80s but 2000-2011 suggests depots are better Kirson 2013
BUT lack of blinding, patients have more clinical contact, depots prescribed to more ill patients, etc. Traditional RCTs show equivalence between oral and depot but more short term and medically adherent patients.

Question 26

What is the clinical impact of side effects?

Answer 26

Stigma
Reduce quality of life
Physical morbidity/mortality
Confounds clinical assessment
Negative attitudes to medication -> poor adherence -> relapses and persistent symptoms

Question 27

What are the side effects of antipsychotics?

Answer 27

Antimuscarinic (anticholinergic) symptoms
Dry mouth
Blurred vision
Cognitive impairment
Constipation
Urinary Retention

Extrapyramidal symptoms
Akathisia
Dystonia
Parkinsonism
Tardive dyskinesia

Metabolic effects
Weight gain
Hyperglyceamia
Dyslipidaemia

Cardiovascular effects
Oedema
Arrhythmia (sometimes QTc related)
Cardiomyopathy
Myocarditis
Postural hypotension

Hyperprolactinaemia
Galactorrhoea
Gynaecomastia
Menstrual abnormalities
Decreased bone mineral density

Miscellaneous adverse effects
Blood dyscrasias
Photosensitivity
Seizures
Sedation
Cerebrovascular events

Question 28

Which receptors are affected in sedation, hypotension and weight gain?

Answer 28

SEDATION
Clozapine and olanzapine have relatively high affinity for H1 receptors, while risperidone has lower affinity.
But anti-adrenergic properties also relevant
HYPOTENSION
Quetiapine, clozapine, risperidone have high a1 receptor affinity, olanzapine has lower a1 receptor affinity
WEIGHT GAIN
?receptor interactions involving serotonin, histamine, dopamine, cannabinoid, histamine (H1), serotonin (5-HT2A, 5-HT2C) muscarinic (M3) and adrenergic receptors.
Possible genetic factors include 5-HT2C receptor gene (HTR2C) and cannabinoid 1 receptor gene (CNR1)

Question 29

What is the difference between Parkinsonism, akathisia, dystonia and tardive dyskinesia?

Answer 29

Parkinsonism is early:
rigidity, tremor, bradykinesia, fatigue, weakness, stiffness, apathy, anhedonia, avolition.
Akathisia: apprehension, dysphoria, irritability, unease, restlessness, inner tension, discomfort, urge to move legs, arms, trunk, etc. difficulty maintaining posture for more than a few minutes, mounting tension when required to stand still, tenson and discomfort in limbs, paraesthesia and unpleasant drawing or pulling sensations in leg muscles. Complex, semi-purposeful stereotypic movements.
Dystonia: abnormal, repetitive movements eg. contorting, twisting muscle spasm, maintained or fleeting,
Trismus, blepharospasm, oculogyric spasm, torticollis, dysarthria, dysphagia, dystonic limb movements and gait, unnerved, sense of something impending, painful, frightening.
Tardive dyskinesia: protrusion or twisting of tongue, smacking, pursing, sucking movements of lips, puffing of cheeks, shewing and lateral movements of jaw, pureposeless, choreiform, often stereotypic trunk and limb dyskinesia, grunting and respiratory arrhythmias, abnormalities of gait and posture. Patients usually unaware.

Question 30

Discuss the CVD risk factors in people with SMI:

Answer 30

Largest relative risk (<5) in dyslipidaemia, but 1.5-3 in obesity, smoking, diabetes, hypertension, metabolic syndrome De Hert 2011

Question 31

What are some risk factors for schizophrenia?

Answer 31

Paternal age
Exposure to influenza/famine while in utero
Obstetric complications, hypoxia
Urban dwelling, low socioeconomic status
Pro-psychotic drugs
Genetics
High grades are protective for schizophrenia McCabe 2010

Hormones - oestrogen possibly has protective role, as women tend to present at about 25-35 and then again at middle age (post-menopausal) and have a better prognosis and are less likely to be impaired by negative symptoms. Women are most likely to relapse in the first 3 months after pregnancy (when oestrogen drops a lot). Correlation of fluctuating estrogen levels with severity of symptoms
Apoptosis in hypothalamic dopaminergic neurons (male mice, no estrogen) – putative sex-specific neurodegenerative processes
Variants in estrogen receptor alpha - association with Schizophrenia
BUT initially oestrogen therapies effective but reversed with longer administration

Question 32

What is the gross pathology of schizophrenia?

Answer 32

Decreased brain weight and volume (especially reduced volume of the hippocampus, amygdala and the parahippocampal gyrus, medial temporal lobes) (MRI studies)
Reduced cortical volume and cortical grey matter
Enlarged ventricles
Decreased activation of frontal lobe and increased activation of temporal lobe (functional neuroimaging studies)

Question 33

What evidence is there for the serotonin hypothesis?

Answer 33

SZ due to excess serotonergic activity
LSD and psilocybin (5HT receptor antagonists) cause positive symptoms in non-schizophrenics
Antagonism at the serotonin 5-HT2 receptor causes reduction in psychotic symptoms
Antipsychotics - SDA (Serotonin-Dopamine antagonists) eg: Clozapine, Risperidone and Sertindole: potent serotonin-related activities

Question 34

What evidence is there for the excitatory amino acids hypothesis?

Answer 34

Insufficient EAAs or receptors (eg NMDA receptors) are implicated in SZ
Low CSF glutamate; decreased glutamate receptors in temporal lobes
Single dose of PCP (non-competitive NMDA receptor antagonist) causes positive and negative symptoms in non-schizophrenics
GWAS: Also GRM3, GRIN2A, SRR, GRIA1 in glutamergic transmission and synaptic plasticity.

Question 35

What evidence is there for the phospholipid membrane hypothesis?

Answer 35

Abnormalities of phospholipid metabolism (neuronal membranes) implicated in SZ
Use of omega-3 fatty acids in SZ (non harmful but if fatty acid deficiency was enough… surely other symptoms too?)

Question 36

What evidence is there for synaptic plasticity problems?

Answer 36

Prats 2016 - Neuregulin 1 associated with synaptic plasticity
Dysbindin and C4A also associated with synaptic plasticity
C4A is expressed more in schizophrenia and it usually targets synapses for pruning by microglia so maybe there is increased synaptic pruning which causes schizophrenia (or effect from other cause?)
Temporal relationship also supports this - schizophrenia usually presents in late adolescence, where there is a lot of synaptic pruning. (But often later as well, especially in women)
Cannabis is also shown to affect the synaptic pruning and has also been associated with schizophrenia - endogenous cannabis increased in schizophrenic patients and acts on CB1 prefrontal cortex - neurocognitive effects in 75%?
Maloku 2009 - doesn’t matter for drugs of abuse, alcohol, duration antipsychotics - less reelin and 20% less Purkinje cells in cerebellum of schizophrenics and bipolar disorder patients. Could explain some of the coordination and tremor symptoms schizophrenic patients have, but not common. Reelin has also been associated with neuronal maturation and function in postnatal brains and dendritic structure formation prenatally and dendritic maturation postnatally.
5 GWAS between 2007-2014 - >100 genome-wide significant loci. Finally found an associated with DRD2.
Also GRM3, GRIN2A, SRR, GRIA1 in glutamergic transmission and synaptic plasticity.
Also CACNA1C (alpha subunit of), CACNB2, CACNA1I - voltage gated calcium channel subunits. Isradipine possibly had effect in bipolar, which also shows mutations in CACNA1C (Osrachter 2014)
miR-137 is a key regulator of neuronal development with roles in neurogenesis and maturation 64,65 and is highly expressed at synapses in the cortex and hippocampus.
Exome sequencing:
Fromer 2014: Enrichment of mutations in genes in ARC (activity-regulared cytoskeleton), NMDAR and FMRP (Fragile X Mental Retardation Protein) pathways
Purcell 2014: Enrichment of mutations in genes in ARC, NMDAR FMRP and calcium signaling pathways again
Kirov: Genes involved in the postsynaptic density (PSD) proteome at synapses. This enrichment was largely explained by genes encoding components of the N-methyl-D-aspartate (NMDA) receptor signaling complex, including members of the disks large family of membrane associated guanylate kinases, and synaptic protein interactors of the activity-regulated cytoskeleton-associated protein (ARC) (also known as Arg3.1) Other genes within schizophrenia-implicated CNVs included CYFIP1, a recently characterized protein binding partner of the fragile X mental retardation protein (FMRP), which together target and regulate the protein translation of a number of identified messenger RNAs (mRNAs) including ARC itself. genes involved in actin filament bundle assembly (F-actin polymerization), a highly dynamic process implicated in the regulation of dendritic spine morphology and synaptic plasticity (37), which interacts with, and is regulated by, NMDA receptor-associated signaling and ARC.
Fromer et al. ( 30) found evidence for an overlap of de novo risk variants in schizophrenia with those seen in ASD and ID and reported evidence for a gradation of mutational severity with ID > ASD > schizophrenia as predicted by a recent model of the relationship between these disorders (71). However, Purcell et al. ( 31) reported no evidence for overlap between these disorders at the individual gene level, though all disorders showed enrichment for FMRP targets.

Question 37

What is the mechanism that relates NMDAR to ARC and FMRP and CYFIP1?

Answer 37

http://www.sciencedirect.com/science/article/pii/S0006322314005198 :
The NMDA receptor complex at the PSD, as well as VGCCs, play a central role in the control of associative plasticity at the synapse through the regulation of calcium entry (42, 43 and 44). The entry of calcium ions into the postsynaptic dendrites through NMDA receptors and VGCCs leads to the activation of a series of second messenger systems, one consequence of which is altered regulation of gene expression through the activation of transcription factors including cyclic adenosine monophosphate response element-binding protein (45 and 46). Through this mechanism, the activation of NMDA receptor and VGCC signaling results in the onset of gene expression at activated synapses, including rapid transcription of the Arc gene, as well as other regulated genes, including BDNF ( 47 and 48). In rodents, Arc mRNA is one of a relatively small number of dendritically targeted mRNAs that accumulate in the region of activated synapses ( 47, 49, 50 and 51). Translation of Arc can thus occur in response to local demands by a process that is regulated by translational inhibition by the FMRP-CYFIP1 protein complex (35), with resultant localization of Arc protein to spines and the PSD (52). Arc has multiple roles in controlling plasticity (53), and blocking Arc activity using antisense oligodeoxynucleotides (ODNs) or transgenic approaches impairs major forms of plasticity, including long-term potentiation (LTP) and long-term depression, and associative memory processes ( 54 and 55). For example, decreasing Arc levels by infusion of Arc antisense ODNs into the hippocampus inhibits brain-derived neurotrophic factor induced LTP and results in a decrease of the formation of F-actin at activated synapses ( 56). Arc also regulates α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor trafficking in the synapse (57), a process that is central to the long-term stabilization of plastic changes ( 58 and 59). stabilizing the molecular and structural events at glutamatergic synapses that are central to plasticity to the sparse spatial and temporal coding of information storage critical for associative memory (65).
However, some implicated genes, including those encoding VGCCs and Neurexin-1 (an associated CNV locus), also exert effects on plasticity presynaptically, pointing to a broader association of risk with synaptic regulation (66 and 67).