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. 1998 Jul 1;18(13):4870-82.
doi: 10.1523/JNEUROSCI.18-13-04870.1998.

Evidence for metabotropic glutamate receptor activation in the induction of depolarization-induced suppression of inhibition in hippocampal CA1

W Morishita  1 , S A Kirov, B E Alger
Affiliations

Evidence for metabotropic glutamate receptor activation in the induction of depolarization-induced suppression of inhibition in hippocampal CA1

W Morishita et al. J Neurosci. .

Abstract

Depolarization-induced suppression of inhibition (DSI) is a transient reduction of GABAA receptor-mediated IPSCs that is mediated by a retrograde signal from principal cells to interneurons. Using whole-cell recordings, we tested the hypothesis that mGluRs are involved in the DSI process in hippocampal CA1, as has been proposed for cerebellar DSI. Group II mGluR agonists failed to affect either evoked monosynaptic IPSCs or DSI, and forskolin, which blocks cerebellar DSI, did not affect CA1 DSI. Group I and group III mGluR agonists reduced IPSCs, but only group I agonists occluded DSI. (S)-MCPG blocked (1S,3R)-ACPD-induced IPSC suppression and markedly reduced DSI, whereas group III antagonists had no effect on DSI. Many other similarities between DSI and the (1S,3R)-ACPD-induced suppression of IPSCs also were found. Our data suggest that a glutamate-like substance released from pyramidal cells could mediate CA1 DSI by reducing GABA release from interneurons via the activation of group I mGluRs.

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Figures

Fig. 1.
Fig. 1.
Activation of mGluRs by (1S,3R)-ACPD reduces DSI of evoked monosynaptic GABAAR-mediated IPSCs recorded from hippocampal CA1 pyramidal cells. A, Illustrated is a control DSI trial on a series of evoked IPSCs (these inward currents are shown as downward deflections). DSI was elicited by a depolarizing voltage step [depolarizing voltage steps (see Materials and Methods) are indicated by filled arrows in all figures] and is represented by the transient reduction of the IPSCs. The center trace is from a DSI trial on the same cell during the fifth minute of bath application of (1S,3R)-ACPD. The IPSCs are reduced in amplitude, and DSI is occluded. The right trace is from a DSI trial recorded 22 min after washout of (1S,3R)-ACPD. B, Recorded from another cell, the first current trace (left) shows the control DSI trial. The center trace shows the effects of (1S,3R)-ACPD (recorded during the fourth minute of bath application). The right traceis from a DSI trial after the stimulation intensity had been increased (ADJ. STIM. INTENSITY) to evoke IPSCs comparable in amplitude to those recorded in control. Note that DSI remains reduced after this manipulation. C, Combined data summarizing the action of (1S,3R)-ACPD on DSI from 10 experiments as in A. In the same graph (separated by the break in the ordinate) are data recorded from a different set of cells summarizing experiments performed as in B. Data in control and recovery are labeled CON and REC, respectively.D, Summarized is the suppression of the IPSC amplitude produced by bath-applied (1S,3R)-ACPD. Data in graphs C and D were obtained from the number of cells shown in parentheses above the bars. Asterisks in the figures indicate significant differences from control values (Student’s paired t test; p < 0.05). In this and other figures stimulus artifacts were blanked for clarity in the display.
Fig. 2.
Fig. 2.
(1S,3R)-ACPD does not affect the amplitude or frequency of TTX-insensitive mIPSCs. Thetop trace illustrates the actions of bath-applied (1S,3R)-ACPD (duration of application is indicated by the solid bar) on a continuous record of spontaneous mIPSCs in the presence of 0.5 μm TTX. (1S,3R)-ACPD produced an inward current of ∼30 pA. A1, Traces of mIPSCs on an expanded time scale recorded during the control period before the application of (1S,3R)-ACPD. A2, Shown are mIPSCs during the sixth minute of (1S,3R)-ACPD perfusion.B1, Corresponding amplitude histograms of the mIPSCs before (filled bars) and in the presence of (1S,3R)-ACPD (open bars). Measurements were taken for 1 min in each condition.B2, Cumulative amplitude distributions obtained in B1 for mIPSCs recorded in control (solid line) and in the presence of (1S,3R)-ACPD (dashed line) for the experiment shown in A. C, Averaged cumulative amplitude distributions of mIPSCs obtained from six cells in control and then in (1S,3R)-ACPD. D, Bar graph shows mean mIPSC frequencies in control and in the presence of (1S,3R)-ACPD (n = 6). (1S,3R)-ACPD had no significant effect on the frequency of mIPSCs. Individual amplitude distributions of events in B2 and C in control and in (1S,3R)-ACPD are not statistically significant, as determined by Kolmogorov–Smirnov tests (p < 0.005).
Fig. 3.
Fig. 3.
Group II mGluRs are not involved in CA1 DSI.A1, Continuous trace of IPSCs showing several DSI trials. Below the trace are averages of five consecutive IPSCs recorded at the indicated time points before (Pre-DSI) and after the voltage step (DSI) in control and in the presence of the specific group II mGluR agonist, DCG-IV, applied at 10 μm (duration of application is indicated by thesolid bar above the continuous trace). Next to the averaged traces is a bar graph summarizing the data from five cells. DSI is not significantly altered by DCG-IV. A2, The graph shows that 1 μm DCG-IV suppressed mossy fiber–CA3 field EPSPs (n = 7 slices) and hence is active under our conditions. EPSPs above the graph are averages of six consecutive responses recorded at the indicated time points from one slice. B, The first trace (left) shows a control DSI trial, and the trial to theright is from the same cell during the eighth minute of application of the group II mGluR agonist, l-CCG-I. Results from six such experiments are shown in the bar graph located to theright of the current traces. l-CCG-I had no effect on DSI.
Fig. 4.
Fig. 4.
Group III mGluRs are not involved in CA1 DSI.A1, The first current trace (left) illustrates two control DSI trials. Thecenter trace shows two DSI trials recorded from the same cell during the fifth minute of application of the group III mGluR agonist, l-AP4. The trials in the right trace also were recorded in l-AP4 after the stimulation intensity had been increased (ADJ. STIM. INTENSITY) to elicit IPSCs comparable in amplitude to those recorded in control. A2, The bar graph summarizes results from 11 experiments similar to those inA1. DSI was not affected significantly byl-AP4. B, An experiment showing that the suppression of CA1 field EPSPs by l-AP4 can be blocked by M-AP4, under our conditions, and hence that M-AP4 is an effective group III antagonist. EPSPs displayed above the graph are averages of six consecutive responses recorded at the indicated time points from one slice. Results from five experiments are summarized in the bar graph to the right. The continuous trace inC shows that M-AP4 (the duration of application is indicated by the solid bar) blocks neither DSI (filled arrows) nor the suppression of IPSCs induced by iontophoresis of (1S,3R)-ACPD (open arrows). Below the trace are IPSCs recorded at the indicated time points before (Pre-DSI) and during DSI (DSI) as well as before (Pre-ACPD) and after (ACPD) iontophoresis of (1S,3R)-ACPD. Individual IPSCs are the averages of five consecutive responses. The bar graph to theright summarizes results from four experiments. (1S,3R)-ACPD was iontophoresed by a −155 nA, 2 sec current. Asterisks denote significant differences from control values.
Fig. 5.
Fig. 5.
Group I mGluR agonists, l-quisqualate and DHPG, reduce the amplitude of evoked monosynaptic IPSCs and occlude DSI. A, The first trace (left) shows the DSI of IPSCs recorded in the control saline. The center trace shows IPSCs recorded during the 10th min of bath application of l-quisqualate (QUIS). Theright trace shows a DSI trial still inl-quisqualate after the stimulation intensity had been increased (ADJ. STIM. INTENSITY) to elicit IPSCs comparable to those in the control condition. B, Illustrated are the effects of DHPG on IPSCs and DSI; trace sequences are as in A. Both l-quisqualate and DHPG suppressed IPSCs and occluded DSI, and the effects persisted even after the stimulation intensity had been increased. C, A graph summarizes the effects of quisqualate and DHPG on DSI.D, A graph shows the effect of these agonists on IPSC amplitudes. Asterisks indicate significant differences from control values.
Fig. 6.
Fig. 6.
Selective block of DSI and the (1S,3R)-ACPD-induced suppression of IPSCs by (S)-MCPG, but not 4CPG. The current trace (CONTROL) in A illustrates the transient suppression of IPSCs during DSI (filled arrows) and after iontophoresis of (1S,3R)-ACPD (open arrows). The trace to the right of control, (MCPG) shows that both forms of IPSC suppression are antagonized during the 12th min of application of (S)-MCPG. The recovery trace shown to the far right was taken 40 min after we started to wash (S)-MCPG from the recording chamber. All current traces in A were recorded from the same cell. To theleft, in the bottom part of A, are IPSCs recorded at the indicated time points before (Pre-DSI) and during (DSI) as well as before (Pre-ACPD) and after (ACPD) iontophoretic application of (1S,3R)-ACPD. The bar graph in thecenter summarizes the results from five cells. The bar graph to the extreme right shows the dose dependence of (S)-MCPG effects on DSI. B, Shown is a continuous record in which the evoked IPSCs were subjected to the same stimulating protocol as in A. Belowthe record are IPSCs recorded at the indicated time points. Note that 4CPG (duration of application is indicated by the solid bar) does not antagonize DSI or the (1S,3R)-ACPD-induced suppression of IPSCs. The bar graph illustrates the results from five cells. IPSCs inA and B are averaged traces from five consecutive responses. (1S,3R)-ACPD was iontophoresed by a −155 nA, 2 sec current. Asterisksindicate significant differences from the control values.
Fig. 7.
Fig. 7.
Agents that block DSI also block (1S,3R)-ACPD-induced depression of evoked monosynaptic IPSCs. A, N-ethylmaleimide (NEM; duration of application is indicated by thesolid line) blocks IPSC suppression induced by iontophoretic application of (1S,3R)-ACPD (open arrows). Below the current trace are IPSCs recorded before (Pre-ACPD) and after (ACPD) iontophoresis of (1S,3R)-ACPD at the indicated time points before (CONTROL) and during (NEM) application of NEM. B1, (1S,3R)-ACPD-induced depression of IPSCs is blocked by 4-aminopyridine (4-AP; duration of application is denoted by the solid line). IPSCs shownbelow the continuous trace were taken at the indicated time points. 4-AP induced large spontaneous inward currents (e.g.,filled diamond), presumed to be GABADresponses (Perrault and Avoli, 1992). B2, 4-AP blocks DSI of evoked IPSCs. IPSCs below the continuous trace were taken before (Pre-DSI) and after (DSI) the depolarizing steps at the indicated time points. Individual IPSCs in A and Bare averages of five consecutive IPSCs. Iontophoresis of (1S,3R)-ACPD (25 mm) inA and B1 was accomplished by a −155 nA, 2 sec current. Large spontaneous inward currents inB2 are truncated to fit the figure.
Fig. 8.
Fig. 8.
(1S,3R)-ACPD does not significantly alter paired-pulse depression of evoked monosynaptic IPSCs. A1, Continuous trace illustrating the effects of bath-applied (1S,3R)-ACPD (duration of application is indicated by the solid bar) on paired-pulse depression (PPD) of IPSCs. Pairs of IPSCs were elicited every 5 sec with an interstimulus interval of 200 msec.Below the continuous trace are IPSCs elicited by the first (filled circle) and second (open circle) stimulus of the paired-pulse stimulation recorded at the indicated time points. In the right records the traces at 1 and 2 are overlapped (offset for ease of comparison) after the first IPSC in 2 was scaled up to match the amplitude of the first IPSC in 1. Note that the ratio of second to first IPSCs does not change in (1S,3R)-ACPD. A2, Plots generated from the experiment in A1illustrating the amplitudes of IPSCs arising from the first (filled circles) and second (open circles) stimulus and corresponding PPD ratio (IPSC2/IPSC1,filled triangles). B, Average PPD ratio obtained from seven cells recorded in control and then in the presence of (1S,3R)-ACPD. The IPSCs illustrated inA1 are averaged from five consecutive IPSC pairs.
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References

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