Schizophrenia neurobiology and treatment

Question 1

Genetics of schizophrenia

Answer 1

Has genetic risk
- Around 50% risk in monozygotic twin

Interaction of genes and environment
- Partial penetrance of genes

Polygenic

Question 2

Genetic and environmental relationship to environment

Answer 2

Genes are susceptible during puberty- when brain is maturing

At birth:

• Obstetric complications
• Prenatal infections
• Nutritional deficiency

All environmental factors that makes genes more susceptible

Adverse life events and substance abuse in adolescence can trigger the disease

Question 3

Neuropathology

- Structural changes

Answer 3

Enlarged ventricles

Reduced brain volume
- Less grey matter in temporal, frontal and subcortex

Cortex and hippocampal cytoarchitectural differences

Question 4

Neuropathology of hallucinations

Answer 4

Paracingulate sulcus morphology

- Shorter length was more present in those with hallucinations

Question 5

Neurodevelopment model of schizophrenia

- Grey matter

Answer 5

During adolescence, grey matter in lost
- Schizophrenic subjects show this is significantly larger

• During pruning, strong synapses were removed along with weak ones
• Chandelier cells are unable to cultivate pyramidal cells during puberty = prefrontal cortex unable to generate synchronised firing

Question 6

Functional changes in schizophrenia

- Hypofrontality

Answer 6

Hypofrontality
- During periods of high cognitive load

Wisconsin card sorting test shows reduced cognitive flexibility
- Does not show increased activity in dorsolateral prefrontal cortex

Question 7

Functional changes

- Hallucinations

Answer 7

Auditory cortex activate occurs during hallucination

Question 8

Neurophysiological changes in schizophrenia [3]

Answer 8

Hypofrontality

• Activity in the dorsolateral prefrontal cortex does not increase during cognition
• Shown with Wisconsin Card sorting test

Hyper-excitable sensory cortex

• Incorrect pruning of synapses
• Causes neurones to fire out of sync

Abnormal neural oscillations
- Lower frequency oscillations and synchrony

Question 9

Diffuse modulatory system affected in schizophrenia

Answer 9

Dopaminergic:

• Nigrostriatal
• Mesolimbic
• Mesocortical

Question 10

Dopamine theory for schizophrenia

- Evidence

Answer 10

Typical antipsychotic drugs prevent positive symptoms
- D2 receptor antagonist

Dopamine agonists [e.g cocaine, amphetamine] can cause positive symptpms

Question 11

D1 receptor family

Answer 11

Gs protein receptors

Includes:
- D1, D5

Question 12

D1 receptor

Answer 12

Part of D1 receptor family
- Gs coupled
Found in
- Caudate
- Putamen
- Nucleus accumbens
- Olfactory tubercule

Question 13

D5 receptor

Answer 13

D1 family of receptors
- Gs protein coupled

Located in:

• Hippocampus
• Hypothalamus

Question 14

Atypical antipsychotics

Answer 14

Specific dopamine antagonist that do not have extrapyramidal effects like typical antipsychotics

E.g

• Clozapine [D4], improves positive and negative symptoms
• Risperidone
• Olanzapine

Question 15

Clozapine side effects [6]

Answer 15

Weight gain

Sedation

Hypersalivation

Tachycardia

Hypotension

Neutropenia

Question 16

Glutamate hypothesis for schizophrenia

- Evidence

Answer 16

PCP [angel dust]: NDMA antagonist

• Causes positive, negative and cognitive symptoms of schizophrenia
• Models schizophrenia in studies

Genetically engineered mice with less NMDA receptors
- Mice show behavioural abnormalities similar to the drug-induced schizophrenia in animals

Question 17

PCP and hypofrontality

Answer 17

PCP is used to model schizophrenia in animal studies

1. PCP antagonises NMDA in the prefrontal cortex
   - Less excitatory firing to the GABA neurones in ventral tegmental area
2. GABA neurones in VTA are less inhibited
   - Dopaminergic projections from VTA to nucleus accumbens are less inhibited
3. Greater DA release = less activation of dopaminergic neurones projecting from the VTA to PFC
   - Less glutamate = hypofrontality

Question 18

Neurocognitive deficits of schizophrenia

Answer 18

Lower IQ

Attentional deficit

Impaired working memory

Planning and information processing deficits