Functional dissection of the CA3-CA1 learning ruleFunctional dissection of the CA3-CA1 learning rule

Sam WangPrinceton University

http://synapse.princeton.edu/~sam/Wang-STDP.ppt

Optical physiology andOptical physiology and synaptic plasticity:synaptic plasticity:

Shari GelberShari GelberDaniel O’ConnorDaniel O’ConnorDmitry SarkisovDmitry SarkisovShy ShohamShy ShohamMegan SullivanMegan SullivanGayle WittenbergGayle Wittenberg

Brain scaling andBrain scaling and evolution:evolution:

Mark BurishMark BurishDamon ClarkDamon ClarkKim Hatch HarrisonKim Hatch HarrisonHao Yuan KuehHao Yuan KuehJennifer ShultzJennifer ShultzMatt WagersMatt WagersKrysta WyattKrysta Wyatt

Laboratory of Sam WangLaboratory of Sam Wang

Too many learning rules!

Abbott and Nelson,Nat. Neurosci.

CA3-CA1 synapse of hippocampus

Rich history of extracellular and single-cell recordingThe cell biology and plasticity literature is vastOne synapse per connectionHas AMPA, NMDA, mGluR,…

Plasticity at CA3-CA1: a separable process?

• Is timing between single spikes sufficient to describe the actual learning rule?

• How different are the requirements for potentiation and depression? Are these full inverses of each other?

• How might the learning rule map to behavior?• Can cell biology help clarify these issues

conceptually?

Questions at the CA3-CA1 synapse

Nishiyama et al. 2000 Nature 408:58480 pairings at 5 Hz Cesium pipet solution

Pike et al. 1999Journal of Physiology 518:57140 pairings at 5 Hz Four epochs (10 pairings each) at 10-s intervals

Christie et al. 1996Learning and Memory 3:160900 pairings at 3 HzEpochs (30-60 pairings each) at 5-s intervals

At the CA3-CA1 synapse, pairing single APs gives…

…LTP.

…no change.

…LTD.

At CA3-CA1 synapses, pairing of single spikes fails to induce potentiation

Single pre+post APs

100 pairings with t=0-7 ms (pre before post)

Pairing frequency 0.1-5 Hz

However…

In Nishiyama et al. Cesium replaced Potassiumin the intracellular pipette solution

This will…-depolarize neuron -block A-type K channels in dendrite-broaden action potentials

Potassium Cesium

Cs+

K+

pairings given at 5 Hz

Cs+

K+

…can bursts of APs emulate Cs+?

LTP induction requires postsynaptic bursting

CA1 neurons fire bursts during theta oscillation

Pairings must be given at high frequency

t

Observations on the LTP learning rule

• Potentiation requires postsynaptic bursts

• Pairings are effective at 5 Hz (near theta)

…does depression have these requirements?

LTD occurs under many timing conditions

All pairings given at 5 Hz

Requirement Theta BurstingLTP yes yesLTD no no

Conclusions so far

• Potentiation and depression have different general induction requirements.– Potentiation: active exploration (causal, bursts, 5 Hz)– Depression: many conditions

• During theta, the rule acts like a phase detector.• At other times, the rule is depression-only.

Why not explore parameter space exhaustively?

…because it’s exhausting!

Shy Shoham

Uncaging in spatial patterns: High-throughput screening of neural responses

Resolution: <1 micron30,000 locations per second

Subthreshold and spiking behavior for “natural” stimulation ensembles

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Now play movie athttp://synapse.princeton.edu/~sam/shoham-oconnor-movie.avi

Local amplification in dendritic branches

Strategies for separating LTD and LTP

LTD and LTP are separable

LTD is fully reversible

LTP is not fully reversible!

After being induced, LTP becomes locked in

The starting distribution of CA3-CA1 synapses

>1 Hz

>10 Hz >10 Hz

The CA3-CA1 learning rule

…butdissectable?

Complex…