2. Plasticity at glutamatergic synapses 1

Question 1

Describe 3 protocols for LTP induction and explain the cellular and synaptic mechanism by which the Hebb’s rule for coincident activity is fulfilled by these stimuli.

Answer 1

1. High-freq stimulation (or repeated low-freq. stimulation): can be done by tetanic stimulation or theta burst stimulation.
2. Spike timing-dependent plasticity: synaptic activation by pre-synapse just before AP-caused depolarization in post-synapse spreads to dendrites -> LTP. Otherway around -> LTD
3. Pairing-induced plasticity???

Question 2

Metaplasticity: concept, mechanisms and significance

Answer 2

1 stimulus can induce different forms of plasticity, depending on previous activity of the synapse (e.g. saturation of post-synapse -> no plasticity possible)
This is modulated by the sliding threshold: perhaps based on changes in dendritic excitability by NMDA-R properties or downstream signaling.

Question 3

What is the signaling pathway initiated by NMDA-R activation, leading to LTP in the CA1 area of hippocampus?

Answer 3

1. NMDA-R mediated influx of Ca2+ and disinhibition of GABAergic connections, which causes even more Ca2+ influx
2. Ca2+ as second messenger causes: activation of protein kinases, calmodulin, less phosphatases and more protease activity.
3. gene expression and protein synthesis
4. synaptic tagging

Question 4

How can postsynaptic calcium as second messenger cause both LTD and LTP induction? What mechanisms control which form of plasticity is induced?

Answer 4

the sliding threshold: distinguishes a certain amount of postcellular activity (Ca influx) to either LTP or LTD.

second messenger function of Ca2+: localization and kinetics determine which effectors are activated -> calmodulin; protein kinases; phosphatases; ion channels; synaptotagmin; other ca2+ binding proteins. Activation of phosphatases causes LTD and activation of kinases causes LTP. Additionally, calcium effectors and coupling of receptors to intracellular mechanisms help to regulate synaptic efficacy.

Question 5

Synaptic tagging hypothesis: what molecular mechanisms serve as synaptic tag

Answer 5

A locally (in spine) generated tag captures a new gene product travelling down the dendritic shaft, brings it into spine -> LTP.
E.g synaptic tags are:
1. persistently active kinases: CaMKII; PKMzeta
2. adhesion molecules, functional prion-like proteins, local dendritic protein synthesis.

E.g molecular mechanism of CaMKII tag:
1. activation because of Ca/Calmodulin
2. autophosphorylation to activate all subunits
3. persistent, calcium-independent activation: capture newly synthesized proteins to active synapse.

Question 6

What are NMDA-R independent forms of plasticity

Answer 6

calcium permaeble AMPA-receptors
metabotropic glutamate receptors
L-type voltage dependent calcium channels

Question 7

what is E-LTP/L-LTP transition:

Answer 7

early to late LTP transition, is activity-dependent regulation of gene expression. convergence of local signaling, causes activation of transcription factors (CREB, Elk1, NFkB) -> changes in gene expression

Question 8

what is inverse synaptic tagging?

Answer 8

INactivity-dependent redistribution of Arc mRNA -> binds to inactive CaMKIIbeta and promotes AMPA endocytosis.

Arc mRNA is promoted after LTP to travel to both active and inactive synapses -> in lower concentrations in active synapses where it stability increases, while in higher concentrations actually causes LTD.