Synaptic Plasticity

A few seconds of stimulation at 100 pulses per second, given to one pathway in the brain of an anaesthetized rabbit, made the cells it reached answer later test pulses more strongly for 30 minutes to 10 hours.

Tim Bliss and Terje Lømo reported this in 1973. A synapse that remembers its use looks like a place to write down experience. To judge that idea, learn to read the recording, what sets the change off, how a synapse is turned down, and how lasting changes differ from brief ones.

The idea: a brief train leaves a lasting change

Bliss and Lømo worked in urethane-anaesthetized rabbits in vivo. They stimulated the perforant path, the bundle of axons that carries input from the entorhinal cortex to the dentate gyrus, and recorded from the dentate gyrus, where the main neurons are small granule cells. Lømo first saw the effect in 1966, in Per Andersen’s laboratory in Oslo, so 1973 is the date of the full report, not of the first observation.

Their electrode sat outside the cells, so it recorded a field potential: the summed current of many neurons at once. A test pulse gives two parts. The population EPSP (field EPSP) is the slow wave made by synaptic current flowing into many granule cells; an EPSP, an excitatory postsynaptic potential, is the depolarization one synapse’s transmitter produces. Its slope or amplitude measures synaptic strength. The population spike is a sharp deflection riding on it, made by granule cells firing together, and its size measures how many fire.

Between test pulses they gave the same fibres conditioning trains; one regimen was 100 stimuli per second for 3 to 4 seconds. The response grew in 15 of 18 rabbits, and the potentiation they reported lasted from 30 minutes to 10 hours. They measured the population EPSP and the population spike separately and suggested that stronger transmission and more excitable granule cells were independent contributors. This lasting rise in synaptic efficacy is long-term potentiation (LTP).

Worked problem, part 1. The numbers in this made-up field recording are illustrative, not data from a paper. Two pathways converge on the same cells. You measure field EPSP slope in mV/ms.

Step 1: baseline. Five test pulses on the test pathway give 0.48, 0.52, 0.50, 0.49 and 0.51 mV/ms. The mean is 2.50 / 5 = 0.50 mV/ms. Every later value is divided by this.

Step 2: after the train. Sixty minutes after a 100 Hz train the slope is 0.80 mV/ms.

percent of baseline = (value after / baseline mean) × 100

0.80 / 0.50 × 100 = 160% of baseline, which is a 60% potentiation. Do not report 160% as the potentiation.

Step 3: the control pathway. The untetanized pathway was 0.51 mV/ms before and 0.50 mV/ms after: 0.50 / 0.51 = 98%. It did not move, so the rise is input specific, confined to the stimulated input, and is not a drift of the whole preparation.

Step 4: the population spike. It grew from 2.0 to 5.0 mV, which is 250% of baseline. That is more than the EPSP rose. The spike is a steep, threshold-dependent function of the EPSP, so a bigger spike alone does not separate the two components. It suggests that excitability rose as well, the component Bliss and Lømo proposed; the clean test compares spike size at matched EPSP size.

The NMDA receptor is the gate for induction

Most mechanism work moved to slices of rat hippocampus, at the synapses that Schaffer collaterals, axons of CA3 pyramidal cells, make onto CA1 pyramidal cells. Separate two steps. Induction is what starts the change; expression is what carries it afterwards.

Glutamate at these synapses acts on two kinds of ionotropic receptor. AMPA receptors carry most of the ordinary EPSP. NMDA receptors pass Na+, K+ and Ca2+, but at resting potential a Mg2+ ion from the extracellular fluid sits in their pore. In 1984 two groups reported this voltage-dependent Mg2+ block: Nowak, Ascher and colleagues in mouse central neurons, and Mayer, Westbrook and Guthrie in mouse spinal cord neurons. The receptor also needs a co-agonist on its GluN1 subunit, glycine or D-serine; in rat CA1 slices D-serine is the co-agonist at synaptic receptors. So an NMDA receptor passes current only when glutamate is bound and the postsynaptic membrane is depolarized enough to drive the Mg2+ out. That makes it a coincidence detector, whose gating ion channels as receptors covers.

Collingridge, Kehl and McLennan tested this in 1983 in rat slices. The NMDA antagonist APV, at doses that abolished responses to an NMDA agonist, left the baseline field EPSP unaffected but prevented LTP after a high-frequency train. NMDA receptors were needed to induce the change, not to carry the everyday response.

Worked problem, part 2. Repeat the made-up experiment with APV in the bath. Baseline is 0.50 mV/ms; sixty minutes after the same train the slope is 0.51 mV/ms. 0.51 / 0.50 = 102%, within the drift of the control pathway. Induction under this protocol was NMDA-receptor dependent.

A large Ca2+ rise in the spine is the trigger. In the canonical model it recruits CaMKII, a kinase that can stay active after Ca2+ falls (see the phosphorylation switch and calcium signaling). Expression includes more AMPA receptors at the synapse: Hayashi, Malinow and colleagues found in 2000 that LTP drove electrophysiologically tagged AMPA receptors into synapses in rat hippocampal neurons. LTP that lasts many hours is thought to need new gene expression, which signaling to the nucleus takes up.

Keep the scope: Harris and Cotman found in 1986 that NMDA antagonists did not block mossy-fibre LTP in guinea-pig CA3. “LTP” names a family of changes.

LTD: the same synapse turned down

In 1992 Serena Dudek and Mark Bear gave the Schaffer collateral input in rat slices 900 stimuli at 1 to 3 Hz. The population EPSP fell and stayed down for more than an hour, only at the conditioned input, and NMDA antagonists prevented it. This is long-term depression (LTD), a lasting fall in synaptic efficacy.

Think of a dimmer switch with one input wire: how much Ca2+ comes through decides the direction. In the canonical model a modest, prolonged Ca2+ rise preferentially recruits protein phosphatases rather than CaMKII. Mulkey, Herron and Malenka found in 1993 that the phosphatase inhibitors okadaic acid or calyculin A blocked LTD induction in rat CA1. Expression includes removal of AMPA receptors by endocytosis (see endocytosis). Receptors cycle all the time: when Lüscher and colleagues blocked endocytosis in CA1 pyramidal cells in 1999, AMPA receptor EPSCs (excitatory postsynaptic currents, the current counterpart of an EPSP) gradually grew. The calcium-amplitude rule is a model, and no single calcium threshold between LTD and LTP is established.

Similar rules shape cortex during development, when vision rewires the visual cortex; ocular dominance and critical-period control cover that.

Short-term plasticity: milliseconds to seconds

Every synapse also changes from one spike to the next. Give two pulses a few to a few hundred milliseconds apart and divide the second response by the first: the paired-pulse ratio. Above 1 is facilitation; below 1 is depression. These changes fade within about a second or a few seconds, and they live mostly in the presynaptic terminal (see synaptic transmission).

Facilitation can raise release for hundreds of milliseconds after one spike. The classic explanation is residual Ca2+: calcium left in the terminal from the first spike adds to the second. In 2016 Jackman, Regehr and colleagues found that deleting synaptotagmin 7 eliminated paired-pulse facilitation at the mouse synapses they tested, although the residual Ca2+ signal was unchanged. Wild-type synaptotagmin 7 restored facilitation and a mutant with a calcium-insensitive C2A domain did not, so at those synapses synaptotagmin 7 is a Ca2+ sensor that reads the leftover calcium.

Depression has a simple candidate: the first spike uses up vesicles.

Worked problem, part 3. Use the simplest depletion model, with these assumptions: no refilling between pulses, no facilitation, a fixed release fraction F and a fixed current per vesicle i. Let F = 0.40, a releasable pool S = 100 vesicles and i = 10 pA. These are teaching values.

EPSC1 = F × S × i

EPSC1 = 0.40 × 100 × 10 pA = 400 pA. The pool left is 100 × (1 − 0.40) = 60 vesicles. EPSC2 = 0.40 × 60 × 10 pA = 240 pA. The ratio is 240 / 400 = 0.60, which equals 1 − F: a 40% depression.

Now the limit. A measured ratio of 0.60 does not prove depletion, since other processes can give the same number, and a simple depletion model cannot explain short-term depression at many synapses. Depression after one spike can recover over seconds.

How the postsynaptic cell adds these weights is the subject of synaptic integration.

From synapse to memory: what the evidence licenses

In 1949 Donald Hebb proposed that when one cell repeatedly helps fire another, the connection between them grows. That is a postulate about what learning needs, not a mechanism. NMDA-receptor LTP fits it, but fitting is not proof.

Three kinds of evidence differ in strength. A correlation: learning goes with potentiation at a pathway. A necessity test: blocking or reversing the change impairs the memory. Morris and colleagues found in 1986 that the NMDA antagonist AP5 infused into the ventricles of rats impaired place learning, spared visual-discrimination learning and suppressed hippocampal LTP in vivo; the drug reached many synapses, so this shows the receptors were needed for both, not that the learning was LTP. A sufficiency test: inducing the change produces the memory’s effect.

The timing rule is also not settled. In 2017 Bittner and colleagues found that in mouse CA1, inputs arriving seconds before or after a dendritic plateau potential could be potentiated, enough to form a place field, the spot in an environment where the cell fires. That rule works over seconds, not the milliseconds of classic Hebbian pairing. How these lessons map onto memory is the business of memory systems, plasticity, networks and consolidation and emotion and stress.

Design problem

Is potentiation at auditory inputs to the lateral amygdala needed for a conditioned fear response? Nabavi, Malinow and colleagues (2014) expressed a light-gated channel in those inputs in rats and used light as the cue. After optical cue-shock pairing, the light suppressed lever pressing. Optical LTD of the inputs abolished the response at testing. Optical LTP given afterwards restored it. LTP in rats never given the pairing produced no response. What do these results show, and what do they not show?