work-storage-byTopic-neuroscience-quals-Q1

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An overview of types of synaptic plasticity in neocortex

Long term plasticity

General stuff: LTP/LTD/STDP protocols alter the amplitude of EPSP evoked by a presynaptic spike of constant amplitude. Classical LTP protocols are associative (the presynaptic activation must be associated with strong postsynaptic activation, often provided by pairing a weak stimulus with a strong one), cooperative (there is a stimulus intensity threshold for LTP inducation; weak stimulation of many afferents may induce LTP even when weak stimulation of one afferent does not), synapse-specific, and NMDA-dependent. Some plasticity protocols haven't been demonstrated in adults yet, and most work more reliably in juveniles.

At least three types of protocols are used:

The STDP results below are from L5-L5 synapses, but some of the non-STDP results are from L2/3. However, the response of neocortical synapses to plasticity protocols depend on the synapse type, and many synapse types behave differently from the following examples. Excitatory synapses onto pyramidal cells in layer 2/3 seem to act similarly to the L5-L5 synapses in many respects, except the STDP timing window for depression seems to be longer. Inhibitory synapses onto L2/3 pyramidal cells seem to have the timing relations in reverse (Holmgren and Zilberter '01). Spiny stellate cells in L4 seem to only do LTD, regardless if the timing is pre-before-post or post-before-pre.

Paired spiking protocols

Here, the response of the synapse depends on (at least) three aspects of the protocol: stimulation frequency, pre- and post- spike timing, and cooperativity (Sjostrom et al '01).

Conventional pairing and simple presynaptic stimulation protocols

Sometimes inhibition must be dampened with a GABA antagonist in order to get LTP.

In contrast to the hippocampus, neocortical LTP also seems to affect short term dynamics; this effect is called synaptic redistribution (Markram and Tsodyks '96).

Before and after undergoing LTP, the synapse may be tested with both high-frequency and low-frequency spike trains. The effect of LTP on the high-frequency spike trains is to only increase the amplitude of EPSPs for the first spikes received, while leaving the steady-state EPSP amplitude the same. However, for low-frequency test trains, the steady-state EPSP amplitude is potentiated too.

It is not known if all forms of neocortical potentiation also evoke synaptic redistribution (rather than only some protocols), or if LTD will reverse the synaptic redistribution.

The mechanism of synaptic redistribution is not certain, but a hypothesis is that there is an increase in presynaptic probability of transmitter release. For the first few spikes in a high-frequency train, or for all the spikes in a low-frequency train, this causes an increase in EPSP amplitude. This depletes the pool of readily releasable vesicles more, though, so that later spikes in a high-frequency train don't show the same potentiation.

All of the mechanisms of STDP in neocortex aren't clearly established. One hypothesis for STDP is that there is an interplay between (postsynaptic) NMDA receptor dynamics and backpropagating action potentials (post-synaptic coincidence detection), which leads ultimately to different timecourses of intracellular calcium in the dendrite. Another hypothesis is that retrograde canniboid signaling allows presynaptic coincidence detection (and that presynaptic NMDA receptors are involved).

Some forms of LTD are dependent on mGluR2 receptors rather than NMDA receptors .

Functions

All of these mechanisms could do all sorts of things. But so far, theorists have used STDP for synaptic normalization, temporal pattern learning, and the formation of synchronizized neural ensembles. Synaptic redistribution has been used for pattern learning.

Synaptic scaling

If you block excitatory transmission in cultured pyramidal cells from visual cortex for two days, the strength of all synapses increases (Turrigiano et al '98). The strength increase is proportional to the original strength of the synapse. The opposite happens if you block inhibitory transmission. This implements what modelers call a "multiplicitive normalization rule". Synaptic scaling is an example of homeostatic plasticity.

The quantal amplitude, that is the size of mEPSCs, changes with these strength increases.

Because experimentally applied glutamate has a greater effect on synapses which have been scaled up, the mechanism is thought to involve an increase in the number of glutamate receptors on the postynaptic neuron. It's unclear if there is a final common path shared by the mechanisms underlying LTP and synaptic scaling.

If the presynaptic neuron is firing at rate $r_{pre}$, the postsynaptic rate is $r_{post}$, and the synaptic weight is $w$, then the effect of synaptic scaling could be modeled by $\frac{dw}{dt} = f(r_{post}) w$, where $f$ is some function that can be either positive or negative depending on $r_{post}$.

Short term plasticity

Short term plasticity is generally thought to be via presynaptic mechanisms.

Short term synaptic depression

Short term depression is an effect where activity temporarily reduces the strength of a synapse. Recent activity causes a reduction in the number of quanta of neurotransmitter released by a presynaptic spike. Depression can be seen by giving a long train of action potentials, and noting the reduction in amplitude of later EPSCs as compared to earlier ones. Cortical short term depression typically has an amplitude of about 20-40% and a timescale of tens to hundreds of milliseconds. However, there appear to be multiple kinds of depression present, with different timescales.

The mechanism is thought to involve, at least in part, depletion of the presynaptic pool of readily releasable vesicles; there are other potential mechanisms, too, which may apply to neocortical synapses.

LTP can modify the short term depression dynamics of a synapse; see synaptic redistribution, above.

Short term synaptic facilitation

Phenomenologically, facilitation is the opposite of depression; it occurs on a similar timescale, but acts to make EPSCs bigger. Facilitation does seem to exist in neocortex (Hempel et al '00).

Like depression, the change in EPSC amplitude is due to a change (in this case, an increase) in the number of quanta released per spike. The mechanism of increase is thought to involve residual Ca$^{2+}$ in the presynaptic synapse, left over from previous spikes.

In other regions, facilitation is further subdivided into two phenomena, F1 and F2, but in neocortex there is not yet enough evidence to do so.

Depression vs. facilitation: who wins out?

Since both facilitation and depression occur on similar timescales, it is possible for one of them to effectively mask the other one; i.e. over the course of a spike train of a few hundred milliseconds, will the EPSCs become bigger or smaller? Depression seems to win more often in cortex in synapses onto pyramidal neurons. Depression dominates more often in neocortex than it does in hippocampus, presumably because neocortical synapses have such a high probability of release initially that there is plenty of room for depression, but not so much room for facilitation.

However, it seems that in synapses onto inhibitory neurons, facilitation may win out.

Augmentation and posttetanic potentiation

Like facilitation, these processes cause increased EPSCs by increasing the number of quanta released from the presynaptic terminal; this in turn is thought to be caused by residual Ca$^{2+}$. The difference is the timescale; neocortical augmentation has a timescale of about 10 seconds, and PTP's is about 70 seconds.

These processes have only been observed in some regions (in synapses onto pyramidal cells in medial prefrontal cortex, but not in visual cortex) (Hempel et al '00). There isn't much evidence separating the two processes in neocortex yet, so to be cautious, people refer to both of them as "augmentation".

Effect of short term plasticity on long-term plasticity

In hippocampus, it appears that short term potentiating plasticity lowers the threshold for the induction of LTP. There is some evidence that this may occur in neocortex , although it's not been fully explored.

\newpage \emph{Please note that we are only permitted to have 5 citations in this paper}

While preparing this paper, I also created a preliminary bibliography of subjects related to the topic, with over 160 citations divided into over 35 cross-linked category listings. In hopes that it may be useful for future researchers, I made it available online as part of a larger database; the entry point is at:

http://purl.net/net/neurowiki/NeocorticalSynapticPlasticity

Chris M. Hempel, Kenichi H. Hartman, X.-J. Wang, Gina G. Turrigiano, and Sacha B. Nelson. Multiple Forms of Short-Term Plasticity at Excitatory Synapses in Rat Medial Prefrontal Cortex. J Neurophysiol Vol. 83 No. 5 May 2000, pp. 3031-3041 (2000)

Carl D. Holmgren, and Yuri Zilberter. Coincident Spiking Activity Induces Long-Term Changes in Inhibition of Neocortical Pyramidal Cells. J. Neurosci. 21: 8270-8277 (2001)

Markram H, Tsodyks M. Redistribution of synaptic efficacy between neocortical pyramidal neurons. Nature. 1996 Aug 29;382(6594):807-10.

Per Jesper Sjostrom, Gina G. Turrigiano and Sacha B. Nelson. Rate, Timing, and Cooperativity Jointly Determine Cortical Synaptic Plasticity. Neuron, Volume 32, Issue 6, 20 December 2001, Pages 1149-1164. (2001)

Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature. 1998 Feb 26;391(6670):892-6.

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