Lecture 27- refinement of synaptic connections II

Question 1

What is the biological mechanism for strengthening and maintaining synapses?

Answer 1

-change in receptors in synapses

Question 2

What are the four glutamate receptors?

Answer 2

-Four kinds, NMDA, AMPA, kainate and metabotropic

Question 3

What do NMDA receptors pass?

Answer 3

-Ca2+, Na+, K+ ions

Question 4

What do AMPA and kainate receptors pass?

Answer 4

• pass Na+ and K+ ions

Question 5

What do metabotropic activate?

Answer 5

-activates second messengers

Question 6

What does glutamat activate?

Answer 6

-Glutamate activates all of the four types of receptors, each can be differentiated by specific drugs that activate them

Question 7

How do AMPA receptors work?

Answer 7

-ions just go through -Na+, K+

Question 8

How do NMDA receptors work?

Answer 8

-Don’t work at resting membrane potential - Blocked by Mg++ ion -the Mg2+ must move= the membrane threshold needs to change -so AMPA change the membrane potential and unblock the NMDA then more ions go through -Ca2+, Na+, K+ go through

Question 9

How do the metabotropic receptors work?

Answer 9

-they are modulatoric receptors, once activated, secondary messengers activated, phospholipase beta 1 is activated and then donstream effects

Question 10

What are the silent synapses?

Answer 10

-Four kinds, NMDA, AMPA, kainate and metabotropic -Some structural synapses are silent (activation has no effect on target cell) - Many glutamatergic synapses have NMDA receptors only, no AMPA - Common in development

Question 11

How does unmasking of silent synapses?

Answer 11

-Depolarizing cell displaces Mg++ ion from pore of NMDA receptor -NMDA receptor can now generate signal -Unmasks previously silent synapse -How does this happen? -Co-­‐ordinated firing of neurons so that cell becomes sufficiently depolarised -Insertion of AMPA receptors -glutamate receptors: four kinds NMDA, AMPA, kainate and metabotropic -dynamic= changes depending on what the system needs

Question 12

What are the concepts in Hebbian synapses?

Answer 12

• Donald Hebb proposed that competition depends on relative timing of activation of synapses
• Neurons that fire together, wire together
• neurons that fire together will always fire together, coordinated firing
• grow more terminals -need coordinated amount of synaptic activity

Question 13

What are some details about Clive Wearing?

Answer 13

• severe amnesia -every single line is new, cannot remember more than 10 seconds -similar to HM except HM had the temporal lobe (including the hippocampus) taken out -Clive wearing had damage in the ability to strengthen synapses thus no long term memory forms

Question 14

What are some details about H.M?

Answer 14

-Bilateral resection of medial structures of the temporal lobe, to treat severe epilepsy (Scoville and Milner, 1957) -Profound impairment of recent memory in absence of other intellectual loss (IQ of 112 post-­‐surgery) -Could not remember what he had for breakfast, find his way around the hospital or recognize anyone he had met since the surgery

Question 15

What did Brenda Milner discover?

Answer 15

-using H.M. as an experimental model discovered the way short term memory is converted to long term memory= refinement of synaptic connections!

Question 16

What does the hippocampus do?

Answer 16

-stores memories

Question 17

What is the experimental technique often used for exploring the temporal lobe?

Answer 17

• electrophysiology
• many conserved areas between mice and humans
• input into dentate gyrus and circles to CA1 and leaves to the cortex
• experimental technique= electrophys= activate the connection between CA3 and CA1 and see if these neurons fire and wire together

Question 18

What is another way of using electrophysiology for research?

Answer 18

• measure how much activity from CA1 when activate CA3
• lot of activation
• LTP=then doesn’t go back to bseline, enhanced activity, will fire more readily later = as the assumption is that it will be needed

Question 19

What is the long term potentiation?

Answer 19

A brief tetanic stimulation of one input results in increased size of subsequent EPSPs (excitatory post synaptic potential) in that input only.

Question 20

What are short term changes with LTP?

Answer 20

• these changes are fast
• AMPA receptors are inserted into the postsynaptic membrane
• the postsynaptic neuron will fire more readily

Question 21

What are the long term changes with LTP?

Answer 21

• if you give many more electircal stimulation= greater form of LTP= late LTP= this is governed by protein synthesis (know as when put in a protein inhibitor then the response disappears)
• electrophysiology= the technique
• have the brain slice in a bath

Question 22

What is the Morris maze test?

Answer 22

-a way to examine memory in mice, tests their ability to tell where they are -but if have a disruption if pclbeta1 then cannot do it

Question 23

What are the types of subunits in NMDA receptors?

Answer 23

• has 4 subunits
• NR1 ia always tehre and NR2A and NR2A interchange and change the confirmation of the receptor
• NR2B is more plastic (in babies)
• NR2A is less plastic

Question 24

What happened in the mice with NMDA receptors knocked out?

Answer 24

-control search for the platform when your remove it= know it should be there -the NMDA receptor mutant doesn’t remember -didn’t have any NMDA receptor

Question 25

What happens to the mice with over-expressed NR2B?

Answer 25

-the NR2B are easier to open= more in babies, more plastic -overexpress the NR2B in mice= mutant= so have more plastic brain -give the mouse an object they explore it -then new object, the control have preference for novel object -control performance levels out after a day -the mutant remembered even after a day! smart mouse!!! -in mice that had increase in NR2B LTP was increased in the mutants

Question 26

What are the steps of LTP?

Answer 26

- Mg++ ion in NMDA receptor displaced by depolarisation of target neuron by AMPA receptors - Allows glutamate to open channel - A low level of stimulation does not depolarise target cell sufficiently to fire action potential - A tetanic burst of stimulation makes the membrane potential negative, close to action potential threshold, displaces Mg++ and allows Ca++ to enter through NMDA channels - Ca++ induces LTP - LTP= it is about depolarization of the cell, need NMDA receptors (if don't have those no LTP)

Question 27

What are the steps of long term depression?

Answer 27

-Certain types of activity can make synapses get weaker rather than stronger -Typically, a low (rather than high) frequency stimulation weakens co-­‐active synapses -Also depends on Ca++ entry (like LTP) -A lot of Ca++ entering causes LTP -A little bit of Ca++ entering causes LTD -AMPA receptor de-­‐phosphorylated, internalised, synapse weakened -just as important as LTP -need to forget! -occurs when low level of activity or not coordinated -calcium dependent, about the system turning OFF

Question 28

How is memory stored?

Answer 28

-via LTP both short term and long term

Question 29

What is does the short term memory need?

Answer 29

-Insertion of AMPA receptors, phosphorylation, enhanced presynaptic release via retrograde signalling (short-­‐term memory) - the early LTP relies on things without protein receptors (insertion of AMPA receptors) the kinases that get activated phosphorylate AMPA= easier to activate then

Question 30

What does long term memory need?

Answer 30

-Protein synthesis, structural changes (long-­‐ term memory) -requires DNA synthesis and needs time -also structural changes

Question 31

What is the story about enriched environment and mice (look at the flashcard in complex functions)?

Answer 31

-mice living in enriched environments=not as bad Huntington's -so maybe enriched environment can help -destiny house -different

Question 32

What was the study about video games?

Answer 32

-Playing action games (in moderation) improves reaction time and focus. -also research into "video games" for mice, teach them to touch a screen with a symbol and receive reward

Question 33

Why is exercising the brain good?

Answer 33

- Release of growth factors (eg BDNF) and generation of new neurons - Improvements in mood and memory - Increased blood flow to brain - Elevated mood - Increased birth of new neurons? - Improves learning and memory? get lot of changes to the brain when exercise! -there is a niche in the hippocampus in the dentate gyrus, new stem cells that can become neurons

Question 34

What is the effect of early physical exercise on stroke victims?

Answer 34

-Very early rehabilitation (\<24 hrs), with an emphasis on mobilisation, may contribute to improved outcomes following stroke. -50% of patients who exercise early are back on their feet within three days Next .... cognitive improvement? -normally they are just in bed and no movement -evidence that exercise helps in stroke patients

Question 35

What is a hot area in brain research at the moment?

Answer 35

-if we could understand all of the critical periods could then maybe develop drug to open the cortical plasticity could then treat autism and schizophrenia etc.

Question 36

More information on critical periods:

Answer 36

-The developing brain exhibits higher plasticity than the adult brain. During normal development, critical periods occur in a predictable temporal sequence, eg. vision, language, and higher cognitive function. 1. Following genetic disruption or pharmacological manipulation, certain critical periods may be accelerated or delayed. Interventions that restore the expected hierarchical progression of critical periods during brain development may then be useful in preempting mental illness. --------- 2. In cases of stroke or other brain injuries suffered during adulthood, the main obstacle to treatment is believed to be the limited plasticity of the adult brain. Thus, a tantalizing treatment strategy would be to rekindle critical period plasticity in the damaged circuits. --------- 3. The ability to tap into critical period plasticity during adulthood, likely through non-­‐invasive means (such as incremental training, enriched environments, or educational video games), could also enhance the potential for lifelong learning.