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. 2011 Nov;21(11):1157-68.
doi: 10.1002/hipo.20815. Epub 2010 Jun 1.

Dentate gyrus granule cell firing patterns can induce mossy fiber long-term potentiation in vitro

Rajen Mistry  1 , Siobhan Dennis, Matthew Frerking, Jack R Mellor
Affiliations

Dentate gyrus granule cell firing patterns can induce mossy fiber long-term potentiation in vitro

Rajen Mistry et al. Hippocampus. 2011 Nov.

Abstract

Hippocampal granule cells transmit information about behaviorally-relevant stimuli to CA3 pyramidal cells via mossy fiber synapses. These synapses express a form of long-term potentiation (mfLTP) that is non-Hebbian and does not require NMDA receptors. mfLTP is thought to be induced and expressed presynaptically, hence, the major determinant of whether mfLTP occurs is activity in the granule cells. However, it remains unclear whether mfLTP can be induced by activity patterns that granule cells exhibit in vivo, and-if so-what context generates these patterns. To address these issues, we examined granule cell activity from in vivo recordings from rats during performance of a delayed nonmatch-to-sample (DNMS) task and found that granule cells exhibit a wide range of spike patterns. In vitro slice experiments in mice demonstrated that some, but not all, of these patterns of activity could induce mfLTP. By further defining the activity thresholds for mfLTP in hippocampal slices, we found that mfLTP can only be induced by spike patterns that fire in high frequency bursts with a low average firing frequency. Using this information, we then screened for suprathreshold bursts of activity during the DNMS task. In a subset of cells, suprathreshold bursts occurred preferentially during the sampling phase of the task. If suprathreshold bursting took place later, during the delay phase, task performance was disrupted. We conclude that mfLTP can be induced by granule cell spike patterns during a memory task, and that the timing of mfLTP induction can predict task performance.

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Figures

Figure 1
Figure 1. Hippocampal granule cells exhibit a wide range of spike patterns and frequencies
a The timing of spikes that occur during consecutive DNMS trials in 4 example granule cells with increasing mean firing frequency (a1, a2, a3 and a4). Timing of spikes is indicated by vertical lines. b The overall inter-spike interval (ISI) histograms for the same cells in (a) demonstrates that bursts of spikes tend to occur in cells with low mean firing frequencies. Note that there is a continuum of firing patterns from low to high frequency in which the cells shift from bimodal to unimodal ISI distributions as the firing frequency increases. c The cumulative relative distribution of mean firing frequencies is shown for all granule cells recorded. d ISI distributions as a function of mean firing frequency are shown for cells grouped together according to mean firing frequency in half log-unit bins. The relative frequency of each ISI shown in pseudocolor. Although cells at the highest and lowest mean firing frequencies have clearly distinct ISI distributions, there is a smooth continuum from one to the other. We note that this distribution distinguishes the population of granule cells in this analysis from the population of CA3 pyramidal cells from the same dataset, which have a substantially smaller representation of short-duration ISIs even at low frequencies of firing (Frerking et al., 2005).
Figure 2
Figure 2. Granule cell firing patterns depend on the number, but not type, of responsive cues
a Mean firing frequency increases as granule cells respond to a larger number of distinct cue-types during the DNMS task (non-responsive cells in black, cells responsive to one cue-type in red, and cells responsive to multiple cue-types in blue). b Mean firing frequency distribution is similar for cells responding only to the sample odor or transit between arms of the maze (sample responsive cells in black, transit responsive cells in red).
Figure 3
Figure 3. Some, but not all, spike patterns recorded from granule cells in vivo can induce mfLTP in vitro
In vivo recordings from 6 different granule cells (a–f) show a range of mean firing frequencies and ISI distributions (top row). Sections of activity were excised to produce similar ISI distributions (second row; the entire duration of granule cell recording was used for cell f). Granule cells that have low mean firing frequencies exhibit pronounced burst firing activity whereas cells with high mean firing frequencies have more regular spike firing patterns as illustrated by the instantaneous spike frequency during the excised section of activity (third row). Spike activity from burst firing granule cells with low mean firing frequencies (a–c) induced mfLTP in slice experiments whereas regular firing cells with high mean firing frequencies (d–f) did not induce LTP (bottom row). The activity shown in the third row was replayed at the time indicated by the arrow for each cell. fEPSP amplitude was recorded for 30 minutes after replay to measure LTP after which the mGluR group II agonist DCG-IV (2 μM) was applied to every slice as a test for the purity of the mossy fibre response. Example traces show the average mossy fibre fEPSP response during baseline (black) and 20–30 minutes after the replay of granule cell activity (red). Scale bars are 0.3 mV (a, e and f), 0.5 mV (b), 0.2 mV (c), 0.15 mV (d), 10 ms.
Figure 4
Figure 4. mfLTP induced by granule cell firing patterns is expressed presynaptically
a mfLTP is induced during whole-cell recording from CA3 pyramidal cells by stimulation with the granule cell firing pattern used in Figure 3a (n = 9). Example traces show response to paired pulse stimulation before (black) and after (red) mfLTP induction. Scale bars are 50 pA and 20 ms. Paired pulse ratio (b) and coefficient of variance (c) are reduced significantly following mfLTP induction.
Figure 5
Figure 5. Induction of mfLTP is dependent on the spike number and frequency during tetanic stimulation
a Systematic variation of the frequency and number of stimuli during the LTP induction protocol revealed the minimum threshold for LTP induction at each frequency. 10 Hz stimulation does not induce mfLTP for 12, 18, 24 and 48 stimuli (n = 5, 5, 6 & 5 respectively). 25 Hz stimulation induced LTP for 12 or more stimuli (n = 8, 8, 6, 6 & 4 for 6, 9, 12, 18 and 24 stimuli respectively). 40 Hz stimulation induced LTP for 12 or more stimuli (n = 11, 12, 8, 5 & 5 for 6, 9, 12, 18 and 24 stimuli respectively). 100 Hz stimulation induced LTP for 9 or more stimuli (n = 7, 5, 5 & 4 for 6, 9, 12 and 18 stimuli respectively). Baseline stimulation frequency was 0.05 Hz. * denotes statistical significance from baseline (p < 0.05). b LTP mesh showing how the amount of LTP (shown in pseudocolor scale) induced depends on the frequency and stimulus number during the high frequency train. Warmer colours indicate increasing amount of LTP.
Figure 6
Figure 6. Induction of mfLTP is dependent on the baseline stimulation frequency
a Mossy fiber synaptic release probability increases with stimulus frequency. Switching stimulation frequency from 0.05 Hz to 1 Hz results in an approximate 4 fold increase in fEPSP amplitude. Scale bars for example traces are 0.3 mV, 10 ms. b mfLTP cannot be induced if the baseline stimulation frequency is 1 Hz but robust LTP is induced when the baseline stimulation frequency is reduced to 0.05 Hz. Scale bars for example traces (black pre-tetanus, red post-tetanus) are 0.4 mV (0.05 Hz), 0.2 mV (1 Hz), 10 ms. c Baseline stimulation frequency must be <0.333 Hz for mfLTP to be induced. LTP is induced at baseline stimulation frequencies of 0.05 Hz and 0.167 Hz (n = 9, 7 respectively) but not at frequencies of 0.333 Hz or 1 Hz (n = 8, 8 respectively). d mfLTP is reversed by switching the stimulation frequency from 0.05 Hz to 1 Hz for 15 minutes immediately after tetanic stimulation. Scale bars for example traces (black pre-tetanus, red post-tetanus and 1 Hz) are 0.3 mV, 10 ms. e Predictions for the amount of LTP induced by natural stimulus patterns calculated from the LTP mesh in Figure 5b agree with observed amounts of LTP found in Figure 3 for each of the 6 patterns tested.
Figure 7
Figure 7. Bursts of activity that would be expected to induce mossy fiber LTP occur in granule cells that respond during the sample phase of the DNMS task
a Raster plots are shown of activity in representative granule cells: one that did not respond to any monitored cues during consecutive trials of the DNMS task (a1), one that responded selectively during the sample phase of the task (a2), and one that responded selectively during movement between arms of the maze (a3). Symbols indicate the time of each spike, with red symbols indicating the initial spike in a burst that crossed the threshold for LTP induction. The average fraction of time spent in each phase of the task (initial (i), sample (s), delay (d) and test (t)) is denoted using dashed vertical lines. Trials were normalized according to both trial and phase duration, to reflect the fact that these time periods varied for each trial. b Thirty representative supra-threshold bursts from a representative cell are shown, aligned at their initial spike (upper traces). The majority of these bursts were caused by relatively high-frequency firing for a very short (~250 ms) period of time. The average of all bursts from the cell is also shown (lower trace), binned into 20 ms intervals. Note that the probability of spiking peaks at multiple spikes in the first 20 ms, then monotonically decays to baseline firing rates. c The amount of predicted LTP induced per hour of recording increases in cells that have a larger proportion short ISIs in the overall ISI distribution. Cells are grouped into those that respond to no cues, those that respond to one type of cue and those that respond to more than one type of cue. d Granule cells that respond during the sample phase but not during transit between arms of the maze are predicted to have significantly more LTP/hr than cells that respond to transit but not during the sample phase. Both populations of cells have similar mean firing frequencies. * p<0.05. e Sample-responsive cells have supra-threshold bursts preferentially during the sampling phase of DNMS trials (black bars). Cells that do not respond to any of the recorded cues fire supra-threshold bursts at random throughout the trials (white bars). * p<0.05.
Figure 8
Figure 8. The timing of bursts that induce mfLTP predicts task performance
a The timing of supra-threshold bursts is shown in a representative cell, phase of the task (initial (i), sample (s), delay (d) and test (t)) is denoted using dashed vertical lines. Different colours indicate whether the trial ended with successful task completion (green) or not (red). Note that most trials with supra-threshold bursts during the delay phase were not completed successfully. This contrasts sharply with the observation that most trials ended with successful task performance (~80%). b The fraction of supra-threshold bursts during trials that ended with incorrect task performance was calculated for different phases of the task; supra-threshold bursting during the delay phase was selectively associated with a substantial increase in errors during the task (n = 26 cells). Dashed line indicates the overall expected task performance in all 26 cells, for comparison. * p<0.05.
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