L4 Schizophrenia: Neurobiology and treatment.

Question 1

Genetic cause of schizophrenia

Answer 1

Approx 50% risk in monozygotic twins

Partial penetrance of genes (interactions of genes and environment)

Polygenic

Question 2

Genes and Environment

Answer 2

Genes are susceptible during puberty- as brain is maturing

At birth

• obstetric complications
• prenatal infection
• nutritional deficiency

Adverse life events and substance abuse in adolescence can trigger the disease (e.g cannabis use - 6x risk)

Question 3

Neuropathology

-Structural changes

Answer 3

-Ventricular enlargement

Reduced brain volume
-less gray matter in temporal lobes, frontal lobes, subcortical structures

-Cytoarchitectural differences in cortex and hippocampus

Question 4

Neuropathology associated with hallucinations

Answer 4

Paracingulate sulcus morphology

-shorter length common in those with hallucinations

Question 5

Neurodevelopmental model of schizophrenia

Answer 5

During adolescence grey matter is lost
-speeds up in early-onset schizophrenia

Pruning- strong synapses removed along with weak ones. Chandelier cells unable to cultivate pyramidal cells during puberty. PFC unable to coordinate firing

Question 6

Hypofrontality

Answer 6

Functional change in schizophrenia

Occurs during periods of high cognitive load

Wisconsin Card Sorting Test shows reduced cognitive flexibility

-no increases in activity in dorsolateral PFC seen in schizophrenics

Question 7

Name one type of functional change seen in schizophrenics during schizophrenics

Answer 7

Auditory cortex activation during hallucinations

Question 8

Describe the neurophysiological changes seen in schizophrenics [3]

Answer 8

Hypofrontality

• no increase in activity in the dorsolateral PFC
• Wisconsin Card Sorting test

Hyper-excitable sensory cortex

• abnormal pruning of synapses
• neurones fire out of sync

Abnormal neural oscillations
-Lower frequency and synchrony

Question 9

Dopamine hypothesis for schizophrenia

Answer 9

Typical antipsychotic (D2 receptor antagonists) drugs prevent positive symptoms
e.g haloperidol

DA agonists can cause positive symptoms
e.g cocaine, amphetamine

Question 10

D1 receptor family

Answer 10

Gs coupled

includes D1 and D5

Question 11

D2 receptor family

Answer 11

Gi coupled

includes D2, D3, D4

Question 12

Atypical antipsychotics

Answer 12

• DA antagonists
• do not have same extra-pyramidal side effects

E.g

• Clozapine [D4] - improves positive and negative symptoms
• Risperidone

Question 13

Side effects of Clozapine

Answer 13

weight gain
sedation
hypersalivation
tachycardia		hypotension
neutropenia

Question 14

Glutamate Hypothesis – evidence

Answer 14

PCP (phencyclidine, angel dust)
-Causes many positive, negative and cognitive symptoms of schizophrenia
-NMDA receptor antagonist
-Genetically engineered mice with
fewer NMDA receptors
-Mice show behavioural abnormalities similar to the drug-induced schizophrenia in animals

Question 15

PCP treatment used to model schizophrenia in animal studies

Answer 15

1) NMDA antagonism in PFC - less glutamatergic firing to VTA GABA neurons
2) Less GABAergic inhibition of VTA-NAcc DA neurons
3) Greater DA release in NAcc
4) Less activation of VTA-PFC DA neurons - less Glu - hypofrontality

Question 16

What do atypical antipsychotics do? [2]

Answer 16

1) Increase DA activity in PFC

2) Decrease DA in NAcc

Question 17

Neurocognitive Deficits in Schizophrenia

Answer 17

1) Lower IQ
2) Attentional deficits (e.g. Stroop Test)
3) Working memory (e.g. Wisconsin Card Sorting Test)
4) Planning and information processing deficits