Gross pathological features of Schizophrenia
- Widespread cortical and hippocampal atrophy - Increased lateral ventricular volume - Loss of grey matter: Reduced dendritic length and spine density on pyramidal neurons
Positive symptoms of schizophrenia
- abnormal behaviour - delusions - illusions - hallucinations - thought disorder
Negative symptoms of schizophrenia
- Alogia (disorganised speech) - Avolition (loss of motivation) - Flattened emotions - Social withdrawal
Cognitive symptoms of schizophrenia
- Leaning and memory - Executive function - Attention
Risk factors for schizophrenia
- Cannabis exposure - Urban living - Stress - Winter birth - Gestational insults such as malnutrition or infection during critical period - 50% heritability
Dopamine hypothesis of schizophrenia
-mesolimibic hyperfunction underlies positive symptoms -mesocortical hypofunction underlies negative and cognitive symptoms
mechanism of typical antipsychotics
E.g. haloperidol; fluphenazine; chlorpromazine - D2 receptor antagonists. D2 receptors are inhibitory pre/post synaptic inhibitory receptors. - Hyperactivity of D2 receptors in the mesolimibic pathway causes positive symptoms - Antagonising D2 receptors therefore alleviates these symptoms
Dopaminergic neurons projecting from the VTA to the nucleus accumbens.
Dopaminergic neurons projecting from the VTA to the prefrontal cortex
Side effects of traditional antipsychotics
Side effects arise through antagonising the inhibitory D2 receptor in the tubularinfandibular and nigrostriatal pathways. - tubularinfandibular: D2 antagonism causes increased prolactin secretion from the pituitary gland, resulting in the development of breasts in males (gynaecomastia) - nigrostriatal D2 antagonism mimics the symptoms of parkinsonism [which normally occur through decreased dopamine release onto D2 receptors in the indirect pathway).
mechanism of atypical antipsychotics
E.g. Olanzapine, risperidone Block of dopamine D2 - or D4 receptor in mesolimbic pathway combat POSITIVE symptoms. [D4 is also an inhibitory dopamine receptor] • D4 - receptor found in mesolimbic pathway, but not nigrostriatal pathway • may explain reduced incidence of extrapyramidal side-effects Some D2 antagonism is necessary as exclusively antagonising D4 receptors produces no efficacy. Also provide some negative symptom relief for unknown reasons.
Side effects of atypical antipsychotics
- weight gain – food craving (5-HT2 antagonism) - Act directly to impair glycemic control causing insulin They avoid tubularinfandibular/extra pyramidal effects due to less D2 antagonism.
Evidence for glutamate hypofunction in schizophrenia
- PCP and ketamine are non-competitive antagonists of the NMDA receptor [block the pore]. They produce positive, negative and cognitive symptoms of schizophrenia.
- NMDA-R knock down mice show stereotyped behaviour, which is reversible with antipsychotic treatment, and cognitive dysfunction
- Many risk genes are related to glutamate transmission However, glutamate levels do not correlate with level of cognitive deficit in patients, suggesting that it is NMDA hypofunction that underlies symptoms rather than glutamate deficit
How does NMDA hypofunction underlie positive symptoms?
Hypofunction at NMDA-Rs removes excitation of GABAergic interneurones, so mesolimbic pathway is dis-inhibited; this leads to positive symptoms [There are other theories - review fast spiking parvalbumin neurones]
How does NMDA hypofunction underlie negative symptoms?
Hypofunction of NMDA-Rs removes stimulation of mesocortical pathway so no DA release in PFC; this leads to negative and cognitive symptoms [There are other circuitry theories - review fast spiking parvalbumin neurones]
Possible therapeutics targets for schizophrenia involving glutamate enhancement?
NMDA agonists may induce excitotoxicity.
More appropriate would be to increase co-agonists which bind the NMDA receptor (D-serine and glycine)
Glyt1 antagonists (glycine transporter channel that reuptakes glycine into neurons and glia)
- ionotropic glutamate receptor - voltage dependent Mg2+ block - Heterotetramer: 2x Constitutive GluN1 subunits with some combination of GluN2A-D/GluN23A-D subunits - GluN1 contains glycine/D-serine co-agonist site - GluN2 contains glutamate site