Theta-burst LTP

Abstract

This review covers the spatial and temporal rules governing induction of hippocampal long-term potentiation (LTP) by theta-burst stimulation. Induction of LTP in field CA1 by high frequency stimulation bursts that resemble the burst discharges (complex-spikes) of hippocampal pyramidal neurons involves a multiple-step mechanism. A single burst is insufficient for LTP induction because it evokes both excitatory and inhibitory currents that partially cancel and limit postsynaptic depolarization. Bursts repeated at the frequency (~5 Hz) of the endogenous theta rhythm induce maximal LTP, primarily because this frequency disables feed-forward inhibition and allows sufficient postsynaptic depolarization to activate voltage-sensitive NMDA receptors. The disinhibitory process, referred to as "priming", involves presynaptic GABA autoreceptors that inhibit GABA release. Activation of NMDA receptors allows a calcium flux into dendritic spines that serves as the proximal trigger for LTP. We include new data showing that theta-burst stimulation is more efficient than other forms of stimulation for LTP induction. In addition, we demonstrate that associative interactions between synapses activated during theta-bursts are limited to major dendritic domains since such interactions occur within apical or basal dendritic trees but not between them. We review evidence that recordings of electrophysiological responses during theta burst stimulation can help to determine if experimental manipulations that affect LTP do so by affecting events antecedent to the induction process, such as NMDA receptor activation, or downstream signaling cascades that result from postsynaptic calcium fluxes. Finally, we argue that theta-burst LTP represents a minimal model for stable, non-decremental LTP that is more sensitive to a variety of experimental manipulations than is LTP induced by other stimulation paradigms. This article is part of a Special Issue entitled SI: Brain and Memory.

Keywords: AMPA; CA1; GABA; Hippocampus; LTP; Long-term potentiation; NMDA; Theta burst stimulation.

Fig. 1

Timing rules for theta-burst LTP. A. CA1 pyramidal neuron with apical and basal dendritic trees that receive excitatory synaptic connections from CA3 via Schaffer collaterals and commissural inputs to both apical and basal dendritic trees. Bursts of high frequency stimulation (S) are used to simulate complex-spike discharges in the afferent neurons. Timing rules are established by varying inter-burst frequency and spatial location of the activated synapses. B. At apical dendritic synapses, bursts repeated at 5 Hz produce optimal LTP. Histogram plots the magnitude of LTP induced by 5–20 bursts repeated at the frequencies indicated on the abscissa. Figure modified from (Larson et al., 1986). A similar frequency dependence is seen at basal dendritic synapses (Capocchi et al., 1992). C. A burst to one apical dendritic input (S1) does not itself produce LTP at those synapses, but primes the cell so that a second burst to a separate input (S2) 200 msec later triggers LTP at only the synapses activated by the second burst. D. A burst to an apical dendritic input (S1) can prime LTP induction at a basal dendritic input (S2). E. A burst to a basal dendritic input (S1) can prime LTP induction at an apical dendritic input (S2). Results depicted in panels C–D–E are from (Larson and Lynch, 1986).

Fig. 2

Multiple-step induction mechanism for theta-burst LTP in field CA1 of hippocampus. A. In the “unprimed state (t=0 msec), afferent stimulation activates a monosynaptic glutamatergic (excitatory) axo-spinous synapse and a disynaptic GABAergic (inhibitory) axo-dendritic synapse on the same pyramidal neuron. Glutamate activates postsynaptic AMPA receptors to depolarize the pyramidal neuron (EPSP) while co-expressed NMDA receptors are blocked by Mg²⁺. GABA activates postsynaptic GABA_A receptors that hyperpolarize the neuron (IPSP). The IPSP curtails the depolarization evoked by the EPSP (EPSP+IPSP). The GAB A released at the inhibitory synapse also activates a slow, metabotropic GABA_B receptor on the presynaptic inhibitory terminal. B. A high frequency burst (theta-burst) under these conditions results in poor temporal summation of the depolarization due to the feed-forward inhibition. C. In the “primed” state (t = 200 msec), There is little change in the synaptic action at the excitatory synapse, but the action of the presynaptic GABA_B receptor produces a use-dependent suppression of GABA release. The diminished IPSP causes the EPSP to have a prolonged depolarizing effect (EPSP+IPSP). D. A high frequency burst in the primed state (primed theta-burst) shows enhanced temporal summation of excitation; the enhanced depolarization allows relief of the Mg²⁺ channel block and a calcium influx through the NMDA receptor.

Fig. 3

Theta-burst stimulation is more efficient than continuous high frequency stimulation for LTP induction in hippocampal field CA1. LTP at apical dendritic synapses was measured as the percent increase in field EPSP slope 60 minutes after LTP induction by stimulation of Schaffer-commissural fibers with either a continuous, 100 Hz train consisting of 8–100 pulses (TETANUS) or the same total number of pulses given as bursts of four repeated at 200 msec intervals (TBS). Significantly greater LTP was evoked by TBS with 20 pulses (5 bursts, p<.05), 40 pulses (10 bursts, p<01), and 100 pulses (25 bursts, p<.01) than tetani consisting of the corresponding number of pulses. Results are from unpublished data by J. Larson and J. Crouch.

Fig. 4

Associative LTP induced by theta-burst stimulation is restricted to major dendritic domains. A. A test electrode (S1) placed in the s. radiatum of field CA1 was used to study the spatial rules governing associative LTP induced by theta-burst stimulation. Stimulus intensity was set to evoke a field EPSP too weak (~1 mV in amplitude) to induce LTP when stimulated with TBS alone (see text for details). Graph shows field EPSP amplitude measured at 20 sec. intervals for 15 min before and 35 min. after TBS (each point is the mean ± s.e.m. of 4 consecutive trials) in seven different slices, each from a different mouse. B. The same test input (S1) was then given TBS simultaneous with TBS to a strong input (S2) to the basal dendrites. The graph shows the S1 response amplitude (as in A) before and after TBS to S1 and S2 (n=7). C. The test input was then given TBS simultaneous with stimulation of a strong input to the apical dendritic field (S2). This resulted in robust LTP to the S1 input (n=6, one slice rejected from analysis due to instability). D. Histograms show field EPSP amplitude measured 30 minutes after TBS, relative to the pre-TBS baseline, in the three stimulation conditions. LTP was significantly greater after the apical-apical pairing than in the other two conditions (**, p<.01). E–F. As in A–D, except that the test input (S1) was to the basal dendrites (n=6 experiments in slices from different mice). Weak stimulation to the basal dendritic input did not induce LTP when stimulated alone (E) or in combination with an apical dendritic input (F), but did show robust LTP after combined stimulation of a strong (S2) basal dendritic input (G). Histograms (H) show that significantly greater LTP was induced after combined basal-basal stimulation than in the other two conditions (**, p<.01). One slice in (E) was rejected from analysis due to instability. In both (C) and (G), the physical location of weak (S1) and strong (S2) electrodes were in subfields CA1c and CA1a, respectively (recording electrode in CA1b), and paired-pulse tests confirmed that the activated fibers were independent. In all other cases, the stimulation electrodes were in CA1c (i.e., the subfield closest to CA3). Results are from unpublished experiments by E. Munkácsy, N. Bartolotti, and J. Larson.

Fig. 5

Within-burst timing and LTP. Hippocampal slices were prepared with a recoding electrode and three stimulating electrodes in s. radiatum of CA1. After a baseline period of recording responses to all three inputs, patterned stimulation was applied as depicted at left. All three inputs received a priming pulse followed by asynchronous bursts. The first pulse in the burst (4 pulses, 100 Hz) to S1 occurred 180 msec after the priming pulse, the first pulse to S2 coincided with the third pulse in the S1 burst, and the first pulse in the S3 burst coincided with the third pulse in the S2 burst. The pattern was repeated ten times at 5 sec. intervals. The LTP induced at all three sets of synapses were statistically different from each other (p<.05). Modified from (Larson and Lynch, 1989).

Fig. 6

Activation of NMDA receptors during theta-burst stimulation. A. The NMDA receptor antagonist, D-AP5 (50 µM) blocks LTP induction by TBS consisting of ten bursts (4 pulses, 100 Hz) repeated at 5 Hz. LTP was measured as the percent increase in field EPSP slope 60 minutes after TBS in the absence of D-AP5 (CTRL) or 60 minutes after TBS given in the presence of the drug (AP5). Data are means + S.E.M. (n=7). B. Field EPSP waveforms evoked by the first two bursts in the TBS under control conditions (CTRL) and in the presence of the antagonist (AP5). The second burst response is larger than the first in both conditions. C. Measurements of the amplitude of the first response within the first burst (left panel) and the total area under the response to the first burst (right panel) were not significantly affected by AP5. D. The areas of bursts 2–10 were calculated and expressed as a percentage of the area of the first burst in both the AP5 condition and the control condition. The NMDA receptor antagonist significantly reduced the area of responses to second through fifth bursts of the TBS (**, p<.01). Unpublished data from J. Larson and J. Crouch.