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ANAT0012 > Schizophrenia > Flashcards

Schizophrenia Flashcards

1
Q

What does SCZ affect?

A

Most basic process of human perception, emotion and judgement

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2
Q

What is SCZ?… and therefore?

A

Heterogeneous disorder with no single defining cause, symptom or sign and can therefore not be diagnosed by a single laboratory test

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3
Q

Social costs?

A

It is highly debilitating and is thus associated with large social costs (£11.8B; Andrews 2012)

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4
Q

First description?

A

Emil Kraeplin (1893), term schizophrenia only later coined (1911) by Eugen Bleuler

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5
Q

Onset?

A

Typically in adolescence or early adulthood and has a lifelong course of illness, with exacerbations, remissions, substantial residual symptoms and functional impairments

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6
Q

Morbidity and mortality?

A

Elevated risk of suicide, 45% attempt and 15% succeed

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7
Q

Positive symptoms

A

Hallucinations, delusions, disorganised thinking/speech, disorganised behaviour, lack of insight

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8
Q

Negative symptoms

A

Blunt (flat) affect, anhedonia, avolition and allogia

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9
Q

Cognitive symptoms

A

Deficits in attention, working memory, learning, verbal fluency, motor speed and executive functions - apparent in first episode patients and relatively static post-presentation (also seen in biological relatives - genetic component)

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10
Q

Changes in brain structure?

A

Ventricular enlargement, reduced brain size and weight (3%), reduced gray matter and cortical volume (4 and 6%): precede first presentation and remain relatively static post-presentation in majority

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11
Q

Other changes in brain structure?

A

Reduced pyramidal neuron cell body size, reduced spine density and impaired synaptic connectivity - absence of inclusion bodies or plaque suggests not neurodegenerative

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12
Q

Once thought to be due to abnormal parenting, now…?

A

Known to have a genetic and environmental component

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13
Q

What is the incidence of SCZ in individuals born to SCZ parents?

A

13-fold higher than that of general population (1%; Gottesman, 1991)

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14
Q

What (and when) did Heston show?

A

In 1966: Compared adopoted-away offspring from SCZ mothers to control group of adoptees - 5 out of 47 adopoted-away developed SCZ, none in control

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15
Q

Twin studies

A

Highlight greater concordance in maternal twins (45%) compared to fraternal twins (15%) - Plomin et al., 1994

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16
Q

Where was DISC1 reciprocal translocation?

A

1q42.1 to 11q14.3 in Scottish pedigree in the 1970s

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17
Q

How many family members expressed the translocation?

A

34/77, 45% of which were diagnosed with schizophrenia, bipolar disorder and recurrent depressive disorder

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18
Q

How does the scottish pedigree illustrate the heterogeneity of the disorder?

A

5/43 without the translocation had psychological indispositions (Blackwood et al., 2001)

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19
Q

What does DISC1 encode?

A

Previously unknow protein called DISC1, further gene linkage studies implicated it’s dysregulation as a susceptibility factor for SCZ

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20
Q

What was found in an American family?

A

Frameshift mutation resulting from a 4bp deletion - SCZ sibling, schizoaffective sibling and unaffected father (Sachs et al., 2005)

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21
Q

DISC1 is widely..

A

expressed in many key brain regions and is developmentally regulated, with highest expression levels in early development

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22
Q

What is DISC1?

A

Intracellular scaffold protein with many protein interactions involved in neuronal proliferation and migration, spine regulation and synapse maintenance (Brandon and Sawa, 2011)

23
Q

What else is DISC1 involved in?

A

AMPAR endo/exocytosis and regulation of NMDAR-mediated glutamatergic transmission

24
Q

What does DISC1 regulate in an activity dependent manner?

A

The access of Kalirin-7 to Rac1, which is important for spine maintenance (Hayashi-Tagaki et al., 2010)

25
Q

What do mouse models expressing the dominant-negative mutation show?

A

Key behavioural features of SCZ and changes in brain structure characteristic of the disorder (Shen et al., 2008)

26
Q

What did Weidong Li et al., (2007) show?

A

Reduced hippocampal dendritic complexity, depressive-like traits, social withdrawal and abnormal spatial memory - only when the mutation was introduced in early postnatal period

27
Q

What does dysregulated DISC1 signalling lead to?

A

Reduced spine density in 2nd and 3rd order dendrites but not later developing 4th and higher order dendrites, emphasizing the critical early postnatal period (Greenhill et al., 2015)

28
Q

How does disrupted DISC1 selectively impair synaptic plasticity?

A

Abolishment of LTP, greatly reduced probability of LTD induction

29
Q

Where does the strongest genetic association arise?

A

MHC locus, specifically an SNP in the C4 gene (Sekar et al., 2016), leading to increased expression as seen in SCZ patients

30
Q

What does C4A do?

A

Because C4A-mediated synaptic pruning occurs during development, excessive complement activity could account for the reduced number of synapses

31
Q

Furthermore, rare CNVs are…

A

established risk factors for schizophrenia, autism and mental retardation

32
Q

Deletion 15q11.2?

A

Found to be strongly associated with SCZ in a large 2017 GWAS - encodes CYFIP1, which together with WRC promotes actin polymerisation and thereby regulates spine maturation and dendritic morphogenesis (Pathania et al., 2014)

33
Q

Where was the dopamine hypothesis derived from?

A

Discovery of typical antipsychotics (e.g. chlorpromazine, haloperidol) in the 1950’s, and obervation that these drugs elicit their effects by blocking the D2R (Carlsson and Lindqvist, 1963)

34
Q

How did stimulant drug abuse provide evidence for the dopamine hypothesis?

A

If taken in high doses and for prolonged period of times, stimulant psychosis, which resembles the positive symptoms of schizophrenia

35
Q

What could reverse stimulant psychosis?

A

Typical antipsychotics

36
Q

What did meta-analyses show?

A

SNP in DRD2 is a risk factor for schizophrenia (Hairong-He et al., 2016) and was identified as a SCZ-associated genetic locus in a 2014 GWAS

37
Q

What was found in 0.3% of SCZ patients?

A

A deletion in 22q11.2 (Rees et al., 2014) - encodes COMT, a catabolic enzyme involved in the breakdown of dopamine

38
Q

What results from the reduced expression of COMT?

A

Increased synaptic levels of dopamine and overstimulation of D2R, schizophrenia-like symptoms

39
Q

What was the glutamate hypothesis derived from?

A

Use of NMDAR antagonists (e.g. ketamine, PCP) reproduced many of the congitive, negative and positive symptoms of SCZ

40
Q

What did NMDAR agonists show?

A

e.g. sarcosine, were used to treat the symptoms of SCZ, showing improvements

41
Q

What did Mohn et al., 1999 show?

A

The reduced expression of NMDAR led to SCZ-like symptoms in mice

42
Q

Where are polymorphisms of NMDAR subunits associated with SCZ typically found?

A

GluN1, GluN2A, GluN2B (Martucci et al., 2006)

43
Q

What evidence is there that the NMDAR is involved in behaviour and cognition?

A

GluN1 mutant mice show social withdrawal and deficits in attention and working memory (Weickert et al., 2013) as well as increased anhedonia and anxiety (Belfort et al., 2010)

44
Q

What do mutations negatively influencing NMDAR subunit expression lead to?

A

NMDAR hypofunction in patients with SCZ

45
Q

While more proximal to the root cause of the disorder…

A

…the glutamate hypothesis does not negate the dopamine hypothesis and the two can be brought together by circuit-based models (Lisman, 2008)

46
Q

Example that dopamine and glutamate hypothesis can be brought together?

A

The reduced activation of PKA resulting from overstimulation of the D2R leads to AMPAR hypophosphorylation and NMDAR hypofunction, which could account for the impairments in synaptic plasticity observed by Greenhil et al., 2015

47
Q

What is the Kraepelinian dichotomy?

A

Broad division of major mood and psychotic illness in adulthood into schizophrenia and bipolar disorder

48
Q

What has undermined the dichotomy?

A

A substantial body of evidence, presented here, has accrued from genetic studies

49
Q

What is schizoaffective disorder characterised by?

A

Abnormal thought processes and unstable mood

50
Q

When is someone diagnosed with schizoaffective disorder?

A

When they show signs of SCZ and bipolar disorder but do not fit the diagnostic criteria for either individually

51
Q

How do the American and Scottish families oppose the dichotomy?

A

Family members showed a variety of neuropsychiatric phenotypes, showing that the disruption of a single gene is not causative

52
Q

What was found in a large population-based study in Swedish families?

A

Substantial overlap in the genetic susceptibility to schizophrenia and bipolar disorder (Lichtenstein, 2009)

53
Q

What else did the population-based study find?

A

Non-shared genetic risk factors consistent with the additive genetic component underlying the pathology of neurodevelopmental psychiatric disorders, including mental retardation, autism, schizophrenia, schizoaffective disorder, bipolar and major depressive disorder.

ANAT0012 (3 decks)

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