Week 10 Flashcards
What are the 2 functions of neurons in the Cortical Subplate located beneath the developing cortex? This is an example of a type of neuron that only have a transient developmental role and are they killed off
- to send out ‘pioneer axons’ into the developing cortical layers to provide guidance cues for other sets of afferents and efferent axons
- to provide temporary synaptic targets for thalamic neurons until other subplate neurons have completed migrations into the cortical layers
- Key point, pioneer neurons
How does testosterone influence neuronal cell death?
Testosterone supresses cell death in the sexually dimorphic nucleus (SDN)
Victor Hamburger came up with the neurotrophic hypothesis. What is this?
That targets of innervation secrete limiting amounts of survival factors to generate a balance between the size of the target organ and the number of innervating neurons
It was found through observing that when a target has been contacted by developing neurons, significant cell death follows that is proportional to the size of the tissue contacted
What two things promote neuronal survival?
- Neurotrophins
- Synaptic transmission! Use of the NMDA receptors specifically
Describe the apoptotic cascade
- Within the cell there is a vast number of transcription factors (Bcl family) acting on the mitochondria to mediate production of Cytochrome C
- When a death signal is detected, Cyt C is produced by the mitochondria
- Cyt C activates Caspase 9, which goes on to activate more
Caspases. - Caspases cause apoptosis
All survival signals and death signals essentially work on the T.Fs in the Bcl-2 family. Pro-death signals promote production of Cyt C and survival signals inhibit it - simple as
An example of a survival factor is Akt. What does it do?
- Phosphorylates BAD preventing it from working
- Also disables FOXO, the T.F responsible for making Puma and Bim (both pro death factors)
How does NMDA activity supress apoptosis?
- Supresses apoptotic machinery such as Caspase 9, 3 and Puma.
What is the role of Puma in apoptosis?
- Puma is sufficient to trigger apoptosis
- Neurons from Puma-KO mice don’t die if NMDAR is blocked
How does LTP work?
- AMPA receptors cause Na+ influx
- Mg ion removed from NMDA receptors causing simultaneous activation of NMDA receptors
- Ca2+ ion influx triggering various intracellular signalling pathways activating protein kinases (CaMKII)
- Activation of these kinases leads to the addition of more AMPA receptors on the postsynapse AND modification of existing AMPAs
What is the role of CREB?
cAMP Response Binding Protein
- Sufficient to induce LTP
What is the mechanism of CREB activation?
- NMDA receptor activation causes Ca2+
- Activates CaMK IV
- Phosphorylates Ser-133
- Activates CBP
- CREB + CBP binds DNA
Coffin-Lowry Syndrome and Rubinstein-Taybi syndrome are due to WHAT?
Both forms of mental retardation arising from mutations in the CREB activation pathway
C-L: Mutation is RSK2 (phosphorylates Ser-133)
R-T: mutation in CBP
What do drosophila with mutations in the CREB activation pathway show?
- Lacking long term memory
- Defective fear conditioning
- Short term memory is unaffected!
What is the methodology of expressing CREB-VP16?
- Tetracyclin T.F is expressed in forebrain neurons that leads to expression of CREB-VP16
- Doxycycline (DOX) binds to tertracycling and prevents it binding to DNA thereby inhibiting the activation of CREB-VP16
- Removal of DOX from the diet leads to expression of the gene!
Discuss the uses of CREB-VP16
- Potent activator of CREB
- Normally a strong stimulus is required to activated CREB, but not when this is present
- CREB-VP16 can convert an early-LTP stimulus to a late-LTP stimulus
- It provides neurons with the gene products necessary for late-LTP
- Is useless unless the neurons are stimulated!
