Cellular NeurobiologyBIPN140

1st Midterm Exam Ready for PickupBy the elevator on the 3rd Floor of Pacific Hall (waiver)

Exam Depot Window at the north entrance to Pacific Hall (no waiver)Mon-Fri, 10:00 AM to 4:00 PM

1st midterm regrade: contact the IA who graded the question before Nov 14, 2016.

PS5 Q&A will be posted on Nov 3rd

Chih-Ying’s Office Hour: Monday, 1:00-2:00 PM, Bonner Hall 4146

PS4 Q&A

Transcriptional Regulation by CREB (Fig. 7.11)

BIPN140 Lecture 11: Synaptic Plasticity (I)

Su (FA16)

1. Short-Term Synaptic Plasticity

2. Long-Term Synaptic Plasticity

3. Molecular Mechanisms of Long-Term Potentiation

Synaptic Facilitation (Fig. 8.1)

AP intervalPaired-pulse facilitation: depends on AP frequency, Ca2+

concentration

Synaptic Depression (Fig. 8.1)

[Ca2+]out = 0.28 mM

[Ca2+]out = 2.5 mM

High frequency APs

Paired-pulse depression: also depends on AP frequency

Augmentation & Potentiation (Fig. 8.1)

Short-term Plasticity at the Neuromuscular Synapse (Fig. 8.2)

Hippocampus (Fig. 8.6)

CA: cornu ammonis (ram’s horn)

LTP is Input-Specific and Persistent (Fig. 8.7)

Tetanus

In vivo recording with embedded electrode

LTP can last for a long time!

LTP is Associative (Fig. 8.9)

Independent stimulation of pathway 1 & 2 Coordinated stimulation of pathway 1 & 2

LTP involves Coincidence Detection (Fig. 8.8)

Mechanism I: NMDA Receptors are Required for LTP (Fig. 8.10)

Mechanism II: Ca2+ influx is Required for LTP (Fig. 8.13)

Addition of Postsynaptic AMPA-Rs during LTP (Fig. 8.12)

2 hr

Hippocampal neurons

Silent Synapses

Silent Synapses (Box. 8B)

The Pre/Post LTP Debate

Lisman, Neuron 63, 281-284, 2009

SuccessFailure

LTP

Probability of SV release

Background: In the cortex, dendritic spines undergo activity-dependent structural remodeling (structural plasticity). What is the link between spine structural changes and LTP? Is it input specific at the level of individual spines? Entirely regulated postsynaptically?

Experiments: Using two-photon photolysis (two-photon uncaging) of caged glutamate to stimulate a single spine at hippocampal CA1 pyramidal neuron (instead of electrical stimulation of Schaffer collaterals). This stimulus protocol completely bypass presynaptic requirement. Test the effect of repetitive uncaging on spine morphology and AMPA/NMDA currents. Test the requirement of CaMKII in activity-dependent spine morphological and electrophysiological changes.

Fig. 1. Spine-head enlargement induced by repetitive uncaging of MNI-glutamate.

Hippocampal Slice

Sparse labeling of CA1 neurons with GFP

Caged glutamate (MNI-glutamate)

Two-photon laser beam: ~1 m (single spine)stimulatedneighboring spineUncaging

Electrical Stimulation (Schaffer collaterals)

Rapid structural change (within ~60s)

Fig. 2. Properties of the spine-head enlargement.

Large spine(> 0.1 m3)

Small spine(< 0.1 m3): silent synapses?

KN62: CaMKII inhibitorAPV: NMDA-R antagonistMCPG: mGluR antagonistW7: calmodulin inhibitorLatA: actin polymerization inhibitor

LTP-like

Fig. 3. Co-localization of enlargement of spine heads and potentiation of AMPA-R current.

Small spineTransient enlargement

Small spineLong-lasting enlargement

AMPA current

AMPA current

Small spineNo spine enlargement

Large spineNo spine enlargement

Whole-cellperforated-patch recording

Fig. 4. Relationship between spine-head enlargement and potentiation of AMPA-R-mediated current.

Early potentiation was detected only at enlarged spines

LTP was induced in spines that showed long-lasting enlargement

Both current potentiation and spine enlargement were detected only in stimulated spines

Whole cell dialysis prevents structural plasticity

Results: Two-photon uncaging of MNI-glutamate allows the location of stimulation to be related directly to the site of spine enlargement (with a resolution at the level of the individual spine). Synaptic potentiation is closely related to enlargement of spine heads in pharmacology, amplitude, time course and spatial localization within the dendrite. Spine enlargement takes place soon after induction, similar to LTP. Spine enlargement may promote accumulation of AMPA-Rs. LTP can be induced at the level of the individual spine, supporting the Hebbian theory. Spines likely act as memory units, whereas larger spines are the physical traces of long-term memory (larger spines are resistant to LTP). Strong support that LTP can occur entirely postsynaptically.