Neurobiology of Schizophrenia

Question 0

What can be seen in CT scan of some patients with schizophrenia?

Answer 0

Enlarged ventricles.

Question 1

3 ways in which schizophrenia is heterogenous?

Answer 1

Symptoms across patients.
Symptoms within one patient across time.
Response to treatment.

Question 2

What can you see in MRI of some patients with schizophrenia?

Answer 2

Reduced gray matter (by 5-10%).

Question 3

What does diffusion tensor imagine (DTI) show in brains of patients with schizophrenia?

Answer 3

White matter tracts are not intact, disorganized.

Question 4

In what part of the brain is grey matter loss most dramatic in patients with schizophrenia? When does this loss occur?

Answer 4

Temporal lobes.

Loss occurs prior to onset of psychotic symptoms.

Question 5

Heritability of schizophrenia?

Answer 5

about 60%

Question 6

What’s the big picture about early environmental risk factors for schizophrenia?

Answer 6

Developmental changes leading to “mis-wiring,” vulnerability to which may be mediated by genetics.

Question 7

2 late environmental risk factors for schizophrenia?

Answer 7

Drug use - Only marijuana was mentioned as causal.

Psychosocial stress.

Question 8

What are 4 specific genes that have been associated with schizophrenia?

Answer 8

DISC1
dysbindin
neuregulin
COMT (recall role in dopamine degradation)

Question 9

What’s an endophenotype?

Answer 9

A measurable result of a gene polymorphism that is not a clinical diagnosis.
E.g. cholesterol levels for LDL receptor polymorphisms.
(heart attacks would NOT count as an endophenotype)

Question 10

What endophenotype relevant to schizophrenia is associated with neuregulin? Define it. How does it change in schizophrenia?

Answer 10

Pre-pulse inhibition.
When you, or mice, hear a soft sound before a loud sound, they have less of a startle reaction to the loud sound.
In schizophrenia, there’s less pre-pulse inhibition. (people startle more easily)

Question 11

Where is dysbinding expressed in the CNS? How does it change in schizophrenia?

Answer 11

Hippocampus.

There’s less of it.

Question 12

With what other protein in dysbindin related? How do dysbinding levels relate to the levels of that protein?

Answer 12

VGlut1.

Less dysbindin -> more VGlut1… and thus more glutamate excitatory signaling in the hippocampus in schizophrenia.

Question 13

What is one hypothesis as to why being born in an urban environment is a risk factor for SZ?

Answer 13

Respiratory infections, such as influenza, that mom gets while pregnant may have negative effects on brain development.

Question 14

What are two physical developmental defects that correlate with SZ?

Answer 14

Cleft-lip/palate and abnormally small posterior nasal volume.

Question 15

What can you see in histology of cortex of DISC1 knockout mice (and upon autopsy of some patients with SZ)?

Answer 15

Impaired neuronal migration into the appropriate cortical layers.

Question 16

What does CNS gene expression look like in broad strokes in SZ patients vs. controls? (2 things)

Answer 16

Underexpression of genes related to synapse formation.

Underexpression of genes related to glutamate and GABA synth.

Question 17

3 pieces of evidence supporting the “dopamine hypothesis”?

Answer 17

1. Antipsychotic efficacy for SZ is correlated with drug’s ability to antagonize the D2 dopamine receptor.
2. Stimulants (cocaine, amphetamines) that increase dopamine can mimic SZ positive psychotic symptoms at high doses.
3. Radioactive labeling of receptors shows higher DA levels in brains of pts with SZ.

Question 18

How do brain dopamine levels correlate with efficacy of antipsychotics for SZ?

Answer 18

The higher the DA levels, the better antipsychotics work.

Question 19

3 factors supporting the glutamate hypothesis?

Answer 19

1. NMDA receptor antagonists (PCP, ketamine) more closely mimic positive and negative symptoms of SZ (vs. DA agonists).
2. NMDA receptor antagonist at cortical interneuron -> glutamatergic hyperactivity of pyramidal cells.
3. Increased glutamate activity can be neurotoxic and cause secondary DA release.
   (dopamine hypothesis can fit under umbrella of glutamate hypothesis)

Question 20

What’s the physiological equivalent of NMDA antagonism (from PCP or ketamine) that actually occurs in the brains of patients with SZ?

Answer 20

Decreased expression of NMDA receptors.

Question 21

What happens if you knock out (or mutate to a “hypomorph,” more accurately) NMDA receptors in mice? Can these effects be reversed with drugs?

Answer 21

They mimic some signs of SZ. Including, memorably, asociality.
Yes, these signs were ameliorated with clozapine.

Question 22

What is “Mismatch Negativity”? How is it useful?

Answer 22

The change in EEG in response to / ability to detect “the odd man out.” Typical test is hearing a series of the same tone occasionally punctuated by a higher pitch tone at random intervals.
It’s an endophenotype for SZ, and highly correlates with GAF score in SZ.

Question 23

Effect of PCP on mismatch negativity?

Answer 23

PCP impairs mismatch negativity.

Question 24

What which step in cortical transmission did the professor emphasize that the defect in SZ is in?

Answer 24

“at the level of interneurons”…

Question 25

What’s a concrete example of “Abnormal Perceptual Integration” in SZ?

Answer 25

Remember the Kanisza Triangle / squares from the vision lectures of B&B part 1? Patients with SZ are less able to see the triangles and squares in these optical illusions. (and this can be objectively seen in measures of brain activity… somehow)

Question 26

Might alterations in GABA signaling in the neocortex also be involved with SZ?

Answer 26

Yeah.