Human synapses show a wide temporal window for spike-timing-dependent plasticity

Abstract

Throughout our lifetime, activity-dependent changes in neuronal connection strength enable the brain to refine neural circuits and learn based on experience. Synapses can bi-directionally alter strength and the magnitude and sign depend on the millisecond timing of presynaptic and postsynaptic action potential firing. Recent findings on laboratory animals have shown that neurons can show a variety of temporal windows for spike-timing-dependent plasticity (STDP). It is unknown what synaptic learning rules exist in human synapses and whether similar temporal windows for STDP at synapses hold true for the human brain. Here, we directly tested in human slices cut from hippocampal tissue removed for surgical treatment of deeper brain structures in drug-resistant epilepsy patients, whether adult human synapses can change strength in response to millisecond timing of pre- and postsynaptic firing. We find that adult human hippocampal synapses can alter synapse strength in response to timed pre- and postsynaptic activity. In contrast to rodent hippocampal synapses, the sign of plasticity does not sharply switch around 0-ms timing. Instead, both positive timing intervals, in which presynaptic firing preceded the postsynaptic action potential, and negative timing intervals, in which postsynaptic firing preceded presynaptic activity down to -80 ms, increase synapse strength (tLTP). Negative timing intervals between -80 to -130 ms induce a lasting reduction of synapse strength (tLTD). Thus, similar to rodent synapses, adult human synapses can show spike-timing-dependent changes in strength. The timing rules of STDP in human hippocampus, however, seem to differ from rodent hippocampus, and suggest a less strict interpretation of Hebb's predictions.

Keywords: Hebbian plasticity; hippocampus; human; neocortex; spike-timing-dependent plasticity; synapse; synaptic plasticity.

Figure 1

Human hippocampal pyramidal (A) and non-pyramidal neuron (B). Top insets show membrane potential changes in response to step current injections. Different scale bars apply to the hyperpolarizing and depolarizing step. Bottom insets show EPSPs in response to extracellular stimulation.

Figure 2

STDP at human excitatory synapses in a hippocampal pyramidal neuron. (A) Schematic representation of the experiment shown in (B–D) with example EPSP and action potential traces. (B) Input resistance calculated from the membrane potential response to a small negative current step delivered through the recording electrode after each EPSP. Grey area indicates the pairing period. (C,D) EPSP amplitude and slope recorded from a hippocampal pyramidal neuron. Same recording as in (B).

Figure 3

Negative timing intervals at which the postsynaptic neuron fired an action potential before the presynaptic stimulus resulted in tLTP. (A) Example EPSPs before and after pairing postsynaptic action potential firing and presynaptic stimulation. (B) Input resistance during the entire recording in (C) and (D). (C,D) EPSP amplitude and slope recorded from a hippocampal pyramidal neuron.

Figure 4

tLTD is induced at negative timing intervals between −80 and −130 ms. (A) Schematic representation of the experiment with example traces. (B) Input resistance during the entire recording period. (C,D) Example of EPSP amplitude and slope recorded from a hippocampal pyramidal neuron. Same recording as in (B).

Figure 5

Single postsynaptic action potentials paired with EPSPs induce STDP in adult human hippocampal neurons. (A) Schematic representation of the experiment with example traces. (B) Input resistance during the entire recording period. (C,D) Single-spike pairing did not alter EPSP amplitude, but induced a small but significant change in slope.

Figure 6

Spike timing window for STDP in human hippocampal synapses.