1. Journal Club April 25 th, 2012

2. Paper Layout Overview Quantal transmission of CA1 synapses Properties of basal transmission: – The GluR1 sub-unit in distance-dependent scaling LTP and postsynaptic insertion of AMPA channels LTP and presynaptic mode of vesicle release LTP and changes in extrasynaptic GluR1 concentration LTP affects synaptic growth and the probability of vesicle release

3. Overview Model of distance-dependent scaling at partially silent distal and proximal synapses Model of early and late phases of LTP

4. Model of distance-dependent scaling at partially silent distal and proximal synapses

5. Model of early and late phases of LTP

6. Paper Layout Overview Quantal transmission of CA1 synapses Properties of basal transmission: – The GluR1 sub-unit in distance-dependent scaling LTP and postsynaptic insertion of AMPA channels LTP and presynaptic mode of vesicle release LTP and changes in extrasynaptic GluR1 concentration LTP affects synaptic growth and the probability of vesicle release

7. Quantal transmission of CA1 synapses Quantal response does not mean opening of all channels at CA1 synapses Quantal size is 10pA (22) Single AMPA channels generate 0.5 -1 pA (23), quantal response is generated by ~ 20 channels

8. Properties relevant to Quantal Transmission Fast rise time indicate that the subset of channels that open at the peak of the response are localized in a hotspot (~100 nm radius) near the location at which the vesicle is re- leased (Fig. 4, A2) (25). This hotspot represents a small fraction of large synapses, which can be up to 1 μm in diameter (18). Only near the site of release is the cleft glutamate concentration in the millimolar range that is required to effectively load the multiple glutamate binding sites on the multimeric AMPARs. Synapse stained to reveal both presynaptic active zone and postsynaptic density shows alignment of the edges of the two structures. [From (52)] Amplitude histograms of evoked responses (minimal stimulation) before LTP induction and shortly afterward. There is reduction in failure probability and increase in quantal size.

9. Model of distance-dependent scaling at partially silent distal and proximal synapses

10. Paper Layout Overview Quantal transmission of CA1 synapses Properties of basal transmission: – The GluR1 sub-unit in distance-dependent scaling LTP and postsynaptic insertion of AMPA channels LTP and presynaptic mode of vesicle release LTP and changes in extrasynaptic GluR1 concentration LTP affects synaptic growth and the probability of vesicle release

11. The GluR1 Subunit in Distance Dependent Scaling C1) Current evoked by glutamate application to excised extrasynaptic membrane is larger distally than proximally and is virtually abolished in the GluR1 knockout. C2) mEPSC amplitude is normally higher distally than proximally, but amplitudes become equal in the GluR1 knockout. [From (12)]

12. Paper Layout Overview Quantal transmission of CA1 synapses Properties of basal transmission: – The GluR1 sub-unit in distance-dependent scaling LTP and postsynaptic insertion of AMPA channels LTP and presynaptic mode of vesicle release LTP and changes in extrasynaptic GluR1 concentration LTP affects synaptic growth and the probability of vesicle release

13. LTP and postsynaptic insertion of AMPA channels (C1) Noise analysis used to estimate number and conductance of AMPA channels in the extrasynaptic membrane before LTP. (C2) Same after LTP. (D1 and D2) Summary data show that LTP produces an increase in channel number but not in conductance. [From (50)]

14. Paper Layout Overview Quantal transmission of CA1 synapses Properties of basal transmission: – The GluR1 sub-unit in distance-dependent scaling LTP and postsynaptic insertion of AMPA channels LTP and presynaptic mode of vesicle release LTP and changes in extrasynaptic GluR1 concentration LTP affects synaptic growth and the probability of vesicle release

15. LTP and presynaptic mode of vesicle release (A1) Before LTP induction, L-AP5 abolishes the NMDA EPSC, indicating low cleft glutamate concentration. (A2) LTP induced by a pairing protocol produces a very large increase in AMPA current. (A3) After LTP induction, the NMDA EPSC is no longer strongly inhibited by L-AP5, suggesting the presence of a higher cleft glutamate concentration. [From (39)]

16. LTP and presynaptic mode of vesicle release (C1) Direct measurement of vesicle release using activity-dependent destaining of FM 1-43 shows faster destaining after LTP induction, indicating enhanced probability of vesicle release. FM 1-43 labels synaptic vesicles. (C2) Statistics before and after LTP induction or control. [From (57)]

17. Paper Layout Overview Quantal transmission of CA1 synapses Properties of basal transmission: – The GluR1 sub-unit in distance-dependent scaling LTP and postsynaptic insertion of AMPA channels LTP and presynaptic mode of vesicle release LTP and changes in extrasynaptic GluR1 concentration LTP affects synaptic growth and the probability of vesicle release

18. Model of distance-dependent scaling at partially silent distal and proximal synapses

19. Model of early and late phases of LTP