Schizophrenia neurotransmitters, cognitive deficits and animal models Flashcards
What receptors do anti-psychotics work on? agonist or antagonist?
Dopamine receptor D2 antagonist
Name the four DA pathways in the brain and where they project from and to? How is this pathway relevant in SZ?
- Mesolimbic dopamine pathway - Ventral tegmental area (A10) projects to the septum, amygdala, hippocampus, ventral striatum and frontal cortex. HYPERACTIVE +ve sym ??
- Mesocortical dopamine pathway- Ventral tegmental area –> neocortex and prefrontal cortex. HYPOACTIVE -ve sym??
- Nigrostriatal dopamine pathway - neurons in the substantia nigra project to dorsal striatum. DORSAL STRIATUM is part of EXTRAPYRAMIDAL MOTOR SYSTEM -> involved in the initiation of movement and this parkinson like symptoms when loose DA. Patients of anti-psychotics have parkinsons like symptoms (tremor, difficulty with movement)
- Tuberoinfundibular dopamine pathway - Hypothalamus to anterior pituitary. DA acts on cells in the pituitary to inhibit prolactin and therefore regulates milk production in lactating mammals. Side effect of antipsychotics is unwanted lactation.
what is the evidence for the dopamine hypothesis of schizophrenia?
- Drugs that increase dopamine (amphetamines) cause psychosis
- All anti-psychotics are D2 receptor antagonists
Dopamine hypothesis originally preposed that schizophrenia caused by an abnormal increase in dopamine levels - far too simplistic. Different DA pathways involved in different aspects of S.Z
What is the evidence that glutamatergic system is involved in schizophrenia?
Drugs that block NMDA receptors can induce psychosis e.g Ketamine and PCP
> Ketamine and PCP causes psychosis and cognitive deficits in normal subjects
exacerbates symptoms in SZ patients.
Thought to be a glutamate HYPOFUNCTION in S.Z
Considerable amount of research demonstrating altered NMDA function, specially hypo function of NMDA receptors.
How does glutamatergic system hypo function affect the rat brain? (model for schizophrenia research)
Cortico-limbic degeneration changes in the rat brain
How is Erb4 implicated in schizophrenia?
Erb4 receptor is a tyrosine kinase receptor co-localised the the PSD with NMDA receptor. Activation and binding of neuregulin to the receptor regulates the activity of the NMDA receptor.
Neuroregulin inhibits NMDA receptor function in the PFC. Increased neuroregulin has been implicated to result in NMDA receptor hypo function.
Neuroregulin-Erb4 signalling has been shown to play a key role in neurodevelopment and neurotransmission, with implications for the pathology of S.Z and post-mortems have demonstrated altered Neuroregulin-Erb4 signalling in the brains of SZ patients.
GU et al. - In rat PFC brain slices. NMDA receptor currents and channel activity considerably reduced after infusion of neuroregulin into the PFC, suggesting an elevated level of neuroregulin contributes to hypo function of NMDA receptors.
Other study (2006) - found increased Erb4-Neuroregulin signalling was associated with suppressed NMDA activation.
How is RGS4 associated with schizophrenia?
RGS4 Inhibits signalling by mGluR5, mGlur5 is localised near NMDA and potentiates NMDA currents.
Mts in this gene lead to changes in mGluR5 interaction with NMDA receptors.
How is GABA neurotransmission implicated in schizophrenia?
The neural mechanisms underlying cognitive deficits in schizophrenia remain essentially unknown. The GABA hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia.
Changes in GABA metabolism changes widely seen in schizophrenia.
- Decreased mRNA for GAD67 (glutamic acid decarboxylase - enzyme that synthesises GABA
- Decreased GABA membrane transporter 1 (GAT1- responsible for reuptake of GABA)
- Changes in GABA cortical interneurons - decreased parvalbumin in fast spiking interneurons in schizophrenia in hippocampus and prefrontal cortex. A study looking at layer 5 labelled PV basket cells showed a 25-30% loss of PV interneurons in comparison to controls.
GABA interneurons are critical for the generation of gamma oscillations and therefore working memory function.
GABAergic system is now a great focus of SZ research.
- GABAa changes implicated to result in hyperfunction of the DA system and problems with sensorimotor functioning
How might cognitive abnormalities be used to improve diagnosis of schizophrenia?
Cognitive symptoms occur early in the disease progression and are often prodromal symptoms and could allow for earlier detection. The cognitive symptoms are the best clinical predictor of outcome.
How has GABA been shown to be involved in aberrant visual perception in schizophrenic patients?
Yoon Study - Study measured the GABA and glutamate levels in the visual cortex of SZ patients and controls in the surround suppression task. SZ patients were found to have around a 10% decrease in GABA levels showing GABA concentration was reduced in the visual cortex, suggesting that GABAergic transmission plays a key role in visual perception in tasks such as the surround suppression task.
How does GABAa interact with DA transmission and how is this linked to SZ?
Sensorimotor processing. Over activation of the DA system is considered to be a major contributor to the disease and this has been associated with alterations in GABA-A functioning and sensorimotor information processing. The dopaminergic is largely under GABAergic inhibitory control mainly via alpha3-GABAa receptors. In alpha3 GABAa KO mice they displayed marked deficits in sensorimotor processing.
What is the delayed match-to-sample task dependant on?
Task depends on sustained firing of the pyramidal cells in PFC and also spiking of interneurons during the delay period.
What changes to W.M do you see in SZ with the n-back task?
- fMRI imaging of the DLPFC during n-back task shows deficits in DLPFC activation during the task. When task progresses in difficulty for 1-back to 2-back, controls show an increased fMRI signal change demonstrating increased activity. However, this increase in activity is not shown in SZ patients, demonstrating a deficit in DLPFC function.
- A more extensive network for memory is demonstrated in controls than SZ patients (seen via fMRI imaging). The network is much more simple in SZ patients and do not see increase and decrease in activity seen in the controls (task performance requires some regions to be activated and some to be suppressed). When controls forget during the task, brain regions were less active. Contrastingly, patients did not show much change in cortical activity whether they got it right or wrong and the complex pattern of activity seen in controls is not seen in SZ patients demonstrating a much more basic cortical network activation during WM tasks in schizophrenic patients.
What other tests can you use to measure executive function in SZ?
- Winconsin card sorting task - subjects asked to match the card to the target card. Subjects told if correct choice and learn rule. Rules shift e.g change from shape to colour to number. This task measures cognitive flexibility. SZ patients do very poorly in the tasks.
- Stoop Test - Measures selective attention, cognitive flexibility, processing speed. Impairement is not specific to schizophrenia as get deficits in addiction, dementia, ADHD and depression but reflects prefrontal deficit.
What brain regions are involved in schizophrenia.
Huge diversity of regions implicates in the pathology of SZ.
- Visual and auditory cortex - hallucinations
- Prefrontal cortex - attention, working memory, cognitive flexibility
- Limbic system - involved in emotion and disturbances seen in schizophrenia (-ve symptoms - deficits also seen in depression)
- Parietal lobe - integrates sensory inputs
- Occipital lobe- processes visual info. Deficits lead to difficulties interpretating complex images/ recognising sz.
- Hippocampus - learning and memory- impaired in SZ.
- Basal Ganglia - movement and emotion - contribute to hallucinations and paranoia and side effects of drugs
