Affective Disorders 2

Question 1

What is the neurotrophin hypothesis of depression?

(2 marks)

Answer 1

• Postulates nueronal plasticity is a key factor in development of depression.
• Serum BDNF is found to be lower in depressed patients

Question 2

What does a decrease in BDNF cause?

(1 mark)

Answer 2

Neuronal atrophy and self pruning

Question 3

How does stress affect BDNF expression?

(1 mark)

Answer 3

Suppresses it

Question 4

Why may BDNF be a biomarker for depression?

Answer 4

Made by platelets in the blood and its expression is lower in depressed patients

Question 5

What is one way to increase BDNF expression levels?

Answer 5

Antidepressants

Question 6

What does mBDNF bind to and what does this activate? What does pre-synaptic depolarisation of mBDNF cause?

(2 marks)

Answer 6

• 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)

Question 7

How does BDNF affect the response to antidepressant Desipramine?

(3 marks)

Answer 7

• 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

Question 8

What does the mutation in BDNF val66met result in?

(3 marks)

Answer 8

• Reduced responsiveness to anxiety
• Increased level anxiety
• Linked to antidepressive responses

Question 9

What happens after a substitution in BDNF occurs?

(in Val66met)

(3 marks)

Answer 9

• Increased sensitivity to stress
• Reduced spine and dendrite complexity in PFC and HFC - diminished synaptic plasticity in HFC
• Resistance to some antidepressants

Question 10

What is adult hippocampal neurogenesis?

(2 marks)

Answer 10

• 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

Question 11

Is AHN increased or decreased by antidepressants?

Answer 11

Increased

Question 12

How is the hippocampus affected by antidepressants in MDD patients?

(1 mark)

Answer 12

Undergoes mass structural remodelling

Question 13

What can be seen in animals that take chronic fluoxetine for 28 days?

(3 marks)

Answer 13

• 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

Question 14

Why is learned helplessness used as a model of depression?

(3 marks)

Answer 14

• 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

Question 15

What factors of ketamine make it a novel antidepressant?

(3 marks)

Answer 15

• IN LOW DOSES
• Partial NMDA antagonist that works in 2 hours
• Partial inhibition of NMDAR
• Found to restore sucrose preference and reduces anhedonia

Question 16

How does ketamine increase the activity of glutamine?#

(2 marks)

Answer 16

• Increases the activity of glutamine through NMDAR and AMPAR activity
• Ketamine blocks NMDAR causing inhibition increasing glutamine downstream and increasing BDNF

Question 17

How does ketamine bind to NDMAR receptor?

(2 marks)

Answer 17

• 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

Question 18

How does ketamine immediately affect the monoamines?

(2 marks)

Answer 18

• 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

Question 19

How is mTOR regulated by the function of ketamine?

(3 marks)

Answer 19

• 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)

Question 20

What can be seen if you inhibit mTORC?

(2 marks)

Answer 20

• Inhibit mTORC by signallling REDD₁ - see decrease in synapse numbers
• Causes helplessness and anhedonic behaviour in absensce of stress response

Question 21

What can sufficient administration of glucocorticoids cause?

(2 mark)

Answer 21

• Atrophy of dendrites and decreased synaptic number in hippocampus and PFC
• Can lead to deficits in GABA neurotransmission

Question 22

What happens to levels of BDNF postmortem in depressed patients?

(1 mark)

Answer 22

• Increase in levels in hippocampus and PFC

Question 23

What do mice with knock in BDNF val66met show?

(1 mark)

Answer 23

• Reduced responsivensss to antidepressants
• Shows you need BDNF for antidepressant response