Affective Disorders 2 Flashcards
What is the neurotrophin hypothesis of depression?
(2 marks)
- Postulates nueronal plasticity is a key factor in development of depression.
- Serum BDNF is found to be lower in depressed patients
What does a decrease in BDNF cause?
(1 mark)
Neuronal atrophy and self pruning
How does stress affect BDNF expression?
(1 mark)
Suppresses it
Why may BDNF be a biomarker for depression?
Made by platelets in the blood and its expression is lower in depressed patients
What is one way to increase BDNF expression levels?
Antidepressants
What does mBDNF bind to and what does this activate? What does pre-synaptic depolarisation of mBDNF cause?
(2 marks)
- mBDNF binds to TrkB receptor - this activation modulatres channels that alter neuronal excitability
- pre-synaptic depolarisation releases BDNF - mediated by TrKB/ERK signalling. TRKB modulates glutamatre release
(post synaptic modulation of glutamate receptors occurs by phoshprylation of NMDAR dubunit NR2B)
How does BDNF affect the response to antidepressant Desipramine?
(3 marks)
- BDNF is required in order to have a signifcant response to desipramine [antidepressants in general]
- In forced swim test, immobility was signficantly lowered with desipramine and presence of BDNF
- When BDNF was KO immobility signifcantly increased in comparison to WT showing BDNF important for correct function of antidepressants
What does the mutation in BDNF val66met result in?
(3 marks)
- Reduced responsiveness to anxiety
- Increased level anxiety
- Linked to antidepressive responses
What happens after a substitution in BDNF occurs?
(in Val66met)
(3 marks)
- Increased sensitivity to stress
- Reduced spine and dendrite complexity in PFC and HFC - diminished synaptic plasticity in HFC
- Resistance to some antidepressants
What is adult hippocampal neurogenesis?
(2 marks)
- Coupled to angiogenesis in neurogenesis and niches in dentate gyrus. Supports role in mechanisms of antidepressants in MDD
- Plays a key role in memory and forgetting
Is AHN increased or decreased by antidepressants?
Increased
How is the hippocampus affected by antidepressants in MDD patients?
(1 mark)
Undergoes mass structural remodelling
What can be seen in animals that take chronic fluoxetine for 28 days?
(3 marks)
- Abberation of post synaptic density and chnge in number and quality of synapse
- Induces delayed structural and molecular adaptions at glutamatergic forebrain synapses that may underline mood improvement
- Shows decreased anxiety and leared helplessness
Why is learned helplessness used as a model of depression?
(3 marks)
- Because a task is inhibited by treatment
- Chronic fluoxetine and SSRIs mimick antidepressant action as it reduces learned helplessness tasks
- E,g, animals freeze less after getting shocks and wont become as depressed
What factors of ketamine make it a novel antidepressant?
(3 marks)
- IN LOW DOSES
- Partial NMDA antagonist that works in 2 hours
- Partial inhibition of NMDAR
- Found to restore sucrose preference and reduces anhedonia
How does ketamine increase the activity of glutamine?#
(2 marks)
- Increases the activity of glutamine through NMDAR and AMPAR activity
- Ketamine blocks NMDAR causing inhibition increasing glutamine downstream and increasing BDNF
How does ketamine bind to NDMAR receptor?
(2 marks)
- Once membrane is more depolarised, Mg2+ is released allowing ketamine to bind to the receptor
- Akt and mTOR pathways leads to trnaslation ind increases in translation proteins
How does ketamine immediately affect the monoamines?
(2 marks)
- decreases GABA and so you get more glutamate and BDNF release
- if drug is given repeatedly can cause accumulatioin of GABA to balance it out
How is mTOR regulated by the function of ketamine?
(3 marks)
- Ketamine increases extracellular glutamate by NMDAR on GABA-ergic interneurons, disinhibitig glutamate transmission
- Leads to activity dependent release of BDNF and stimulation of signallling cascades including Akt which activates mTOR translational system in dendrites of neurons
- Induction translation causes increased levels of GluR1 and other synaptic proteins providing machinery required for increased synaptogenesis and spine formation
- (Effects contribute to rapid and sustained antidepressant actions of ketamine)
What can be seen if you inhibit mTORC?
(2 marks)
- Inhibit mTORC by signallling REDD1 - see decrease in synapse numbers
- Causes helplessness and anhedonic behaviour in absensce of stress response
What can sufficient administration of glucocorticoids cause?
(2 mark)
- Atrophy of dendrites and decreased synaptic number in hippocampus and PFC
- Can lead to deficits in GABA neurotransmission
What happens to levels of BDNF postmortem in depressed patients?
(1 mark)
- Increase in levels in hippocampus and PFC
What do mice with knock in BDNF val66met show?
(1 mark)
- Reduced responsivensss to antidepressants
- Shows you need BDNF for antidepressant response
