BS42018 L3+4 Flashcards
what frequency (Hz) distinguishes between induction of LTD and LTP?
8Hz
what do different firing frequencies do regarding synaptic plasticity?
different firing frequencies will produce different levels of NMDAR activation
this dictates the level of intracellular calcium that enters the post-synaptic cell and also dictates whether you see persistent depression or LTP
what are the three temporal phases of LTP?
- Dependent on post-translational modification of existing protein- ie. Phosphorylation
- Dependent on synthesis of new protein from existing mRNA- ie. mRNA translation
- Dependent on synthesis of new protein and new mRNA- ie. Gene transcription, so involves the nucleus rather than the synapse perse
what are the timescales of the three temporal phases of LTP?
phosphorylation- occurs after first hour of stimulation
mRNA translation- occurs between hours 1-2
gene transcription- occurs 3+ hours after stimulation
how can you inhibit the early phase of LTP?
by inhibiting a variety of kinases that have shown to phosphorylate proteins at the synapse
these include- PKA, PKC, PKG, ERL, CAMKII, PYK2, Fyn
what does activation of Ca2+ dependent kinases do?
induce LTP
what does activation of phosphatases do?
induce LTD
give examples of approaches used to identify protein involvement or specific targets in LTP (4)
- receptor antagonists
- enzyme inhibitors
- knockout mice
- use of inactive/dominant negative forms
give a specific example of a knockout model used to investigate protein involvement in LTP
CAMKII a-subunit knockout mouse
what did the CAMKII a-subunit knockout model show?
not only CAMKII is involved as there was still amplitude
what are the mechanisms for the maintenance of early phase synaptic plasticity?
phosphorylation of receptors
receptor trafficking
which serine residue is down regulated after LTD in GluA1 subunits?
S845
what happens to ser831 after LTP in GluA1 subunits?
the level of phosphorylation is upregulated
under resting conditions what are the states of s845 and s831?
s845 is phosphorylated
s831 is dephosphorylated
what functional effects does LTP have on AMPARs?
increased conductance and increased trafficking to membrane
what is the evidence that GluA receptors traffic during LTP?
indirect- from studies that block post-synaptic interactions with regulatory/trafficking proteins eg PICK/GRIP etc. also evidence from silent synapses.
Direct- from immunohistochemical detection of surface GluA receptors (culture) and from imaging fluorescent GluA chimeras (eg. SEP-GluA1).
why is phosphorylation not a sufficient long term LTP solution?
it is heavily reliant on being driven by kinase and phosphorylation of AMPA receptors and most kinases don’t function long term enough to be able to drive changes that are able to last for weeks or months.
where is the mRNA involved in phase II of synaptic plasticity (mRNA/local protein synthesis) likely to be located?
in the dendrites to maintain synaptic specificity of plasticity
where is the mRNA involved in phase II of synaptic plasticity (mRNA/local protein synthesis) likely to be located?
in the dendrites to maintain synaptic specificity of plasticity
stimulation of protein synthesis from mRNAs could involve; (3)
- Inhibition of mRNA degradation, leading to elevated mRNA levels (observed), and increased synthesis of the corresponding protein (if the mRNA levels are rate-limiting).
- Phosphorylation of ribosomal proteins near the synapse (observed), leading to more efficient translation of the mRNA.
- Phosphorylation of ribosomal proteins is triggered by ERK.
how would you alter the number of glutamate receptors on the post synaptic membrane?
Phase 1; increase protein delivery, membrane insertion/trafficking and via lateral mobility
Phase 2 and 3; increase protein synthesis, local protein synthesis and somatic synthesis (general protein trafficking).
gene transcription is activated by transcription factors. what types of TFs are there?
constitutive TFs, inducible TFs.
give examples of constitutive and inducible TFs
constitutive- CREB, Elk1, NFkappaB
inducible- egr1, junB?
what happens rapidly after triggering of synaptic plasticity?
morphological changes
