Park JY , Remy S , Varela J , Cooper DC , Chung S , Kang HW , Lee JH , Spruston N .

MH-074866 NIMH NIH HHS, NS-35180 NINDS NIH HHS , R01 NS035180-15 NINDS NIH HHS , K01 DA017750 NIDA NIH HHS , R01 DA024040 NIDA NIH HHS , R03 DA023719 NIDA NIH HHS , R01 NS035180 NINDS NIH HHS , P50 MH074866 NIMH NIH HHS

	Figure 1. Activation of group I mGluRs enhances excitability of CA1 pyramidal neurons.(A) Responses to step current injections of 300 pA for 0.6 s (left) or 400 pA for 4.5 s (right). Black traces are control responses in normal ACSF, just before the onset of DHPG perfusion (t = 0 min). Red traces are after 15 min (t = 15 min) of application of 2 µM DHPG (see Materials and Methods). (B) Responses to noisy current injection (200 pA step plus noise for 10 s; first 6 s shown). (C) Number of action potentials evoked by 10-s long, noisy current injections before (t = 0 min) and after (t = 15 min) application of DHPG (paired t test, p<0.001). (D) Expanded plot of the initial portion of response shown in (B). Note the lack of effect of DHPG on subthreshold responses prior to the first spike. (E) Response to five brief current injections (2 nA, 2 ms each) to evoke a burst of action potentials in control (t = 0 min) or DHPG (t = 15 min). First arrow indicates peak of the post-burst ADP in DHPG and second arrow indicates time of decay to 25% of peak. (F) Responses to step current injections (800 pA, 50 ms) to evoke a burst of action potentials, with and without a second step (200 pA, 20 ms) to test for excitability during the post-burst ADP.
	Figure 2. Metabotropic glutamate receptors mediating the DHPG-induced ADP.(A) Top: sample responses to bursts of five action potentials in normal ACSF (black) or following application of 2.5 µM DHPG (red) in four different conditions. Drug concentrations are 25 µM LY367385 and 10 µM MPEP. Bottom: time course of medium ADP amplitude (58 ms after last spike) following application of 2–4 µM DHPG beginning at t = 0 min. (B) Post-burst potential plotted over time in normal ACSF. On select trials, 500 µM DHPG was applied locally, via pressure application from a broken patch pipette (see Materials and Methods) approximately 3 s before the current-injection stimulus. Blue arrows and traces indicate application to the distal apical dendrites (near the border of stratum radiatum and stratum lacunosum-moleculare); red arrows and traces indicate application to the perisomatic region (stratum pyramidale). (C) Same as (B) except 2–4 µM DHPG was applied to the bath beginning at t = 0 min and normal ACSF was applied using localized pressure application to the perisomatic (red) or apical dendritic (blue) regions. In all panels, the stimulus is five brief current injections and the interval between trials is 20 s. Action potentials are truncated.
	Figure 3. Synaptic stimulation during somatic action potentials induces a post-burst ADP.(A) Synaptic stimulation (SYN) was paired with somatic action potentials (AP) to evoke the post-burst ADP. Stimuli were 100 Hz five action potentials only, 50 Hz for 1 s of synaptic stimulation only, or both stimuli combined together. Examples for each condition from a single cell are overlaid on the right. (B) Time course of the change in post-burst potential in control and group I mGluR receptor antagonists. Representative average responses were obtained from three consecutive traces in control and MPEP/LY. Arrows indicate the amplitude of the change in post-burst potentials. The baseline membrane potential is indicated by dotted lines. (C) Normalized change in post-burst potential in control and MPEP/LY (n = 5 cells in each condition; results for each cell are shown by the lightly colored lines).
	Figure 4. The post-burst ADP induced by DHPG requires action potential firing or a calcium spike.(A) Responses to step current injections (0.5 or 2.0 nA, 40 ms) in various conditions, as indicated. Note the calcium spike in response to the larger current injection in the presence of TTX (0.5 µM). Action potentials are truncated in the first two traces. Gray traces are superimpositions of the previous response. (B) Summary of experiments like the example shown in (A). Interval between trials is 20 s. (C) Effects of step current amplitude (top: 0.5, 1.0, 1.5, 2.0 nA for 40 ms) and duration (bottom: 1.5 nA for 20, 30, 60, 100 ms) on calcium spikes and the resultant ADP. (D) Summary of experiments like the example shown in (C).
	Figure 5. The post-burst ADP induced by DHPG requires extracellular calcium entry.(A) Responses in control (t = 0 min, black), ACSF with 2–4 µM DHPG and 2 mM Ca2+ (red) and ACSF with 2–4 µM DHPG and zero Ca2+ (blue). Time course of the experiment and summary data are also shown (*** paired t test, p<0.0001). (B) Sample responses and time courses for experiments to test effects of nimodipine (10 µM) and NiCl2 (Ni, 50 µM) on the DHPG-induced post-burst ADP. (C) Summary of effects of nimodipine (Nim) and NiCl2 (Ni) in DHPG alone (2–4 µM; t = 12 min) and DHPG plus drug (t = 25 min). (D) Ratio of post-burst ADP at t = 25 min to ADP at t = 12 min. Note that this ratio is greater than one in control, because DHPG increases the amplitude of the post-burst ADP over this time. One-way ANOVA, p<0.0001, with post hoc tests versus control: ** p<0.001. (E) Concentration dependence of the block of the post-burst ADP by Ni2+. Values are normalized to the control ratio in (D).
	Figure 6. The post-burst ADP induced by DHPG is voltage dependent.(A) Responses in normal ACSF (control, black) and 2.5 µM DHPG at holding potentials of −65, −75, and −85 mV (red, blue, and green). Below are subtractions of the control response from the DHPG response for each pair, clearly revealing a voltage-dependent medium ADP (mADP) and a voltage-independent slow ADP (sADP). Stimulus is five brief current stimuli (as in Figure 1E) and action potentials are truncated. (B) Summary of experiments like the one shown in (A). Hyperpolarization decreased the post-burst AHP in control and decreased the post-burst medium ADP in DHPG (repeated-measures one-way ANOVA, p<0.0001 for effect of holding potential in both control and DHPG). Holding potentials were −65.4±0.2 mV, −75.4±0.2 mV, −85.8±0.2 mV in control (n = 6) and −65.9±0.2 mV, −75.6±0.2 mV, −85.6±0.2 mV in DHPG (n = 10). Inhibition of the medium ADP by hyperpolarization, plotted as a percentage of the medium ADP amplitude (right). (C) Responses in 2.5 µM DHPG to three stimuli: five brief depolarizing current injections (black), one hyperpolarizing current injection (black, truncated, returned to baseline at arrow), or both combined (blue). (D) Top: the post-burst ADP in DHPG is compared to the linear sum (red) of the post-burst ADP and the hyperpolarizing response. Bottom: the post-burst ADP is compared to the combined response (blue). The hyperpolarizing response was delivered either 8 ms (early step) or 48 ms (late step) after the last action potential. The amplitude of the response (arrows) was measured at the time when the hyperpolarizing response decayed back to rest, which was 54 ms (early step) or 100 ms (late step) after the last action potential. Action potentials are truncated. (E) Comparison of the expected response (from linear sum, red) and the actual response amplitude (blue) for the early step (54 ms) and late step (100 ms). Paired t test: *** p<0.0001 for 54 ms, p = 0.18 for 100 ms. (F) Inhibition of the medium ADP by the early and late hyperpolarization, plotted as a percentage of the medium ADP amplitude.
	Figure 7. Post-burst depolarization only activates Ni2+-sensitive Ca2+ channels during mGluR activation.(A) The DHPG-induced medium ADP is blocked by application of 500 µM Ni2+, but an artificial medium ADP produced by a ramp current injection after the spikes is unaffected by Ni2+. (B) Summary of Ni2+ effects on ramp-induced medium ADP. Paired t test, p = 0.14. (C) A variable ramp current produced a linearly increasing medium ADP. (D) Summary plot showing a linear effect of the ramp-current amplitude (IRamp, initial amplitude) on post-burst potential.
	Figure 8. Cav2.3 knockout mice exhibit a reduced DHPG-induced medium ADP compared to wild-type mice.(A) Examples of responses in control (black) and following application of 10 µM effect of DHPG (red, blue) in wild-type (WT) and Cav2.3 knockout (KO) mice. Stimulus is five brief current stimuli (as in Figure 1E). Action potentials are truncated. (B) Time course of effects of DHPG in WT (red) and Cav2.3 KO (blue) mice. Interval between trials is 20 s. (C) Summary of effects of DHPG on medium ADP in WT (red) and Cav2.3 KO (blue) mice. Unpaired t test: ** p<0.001.
	Figure 9. Voltage-clamp analysis of voltage-gated calcium channel modulation by DHPG.(A) Voltage-clamped Ca2+ currents in CA1 pyramidal neurons. DHPG enhances currents evoked by steps from −70 to 0 mV (5 µM DHPG, red; control, black), but not to −40 mV (5 µM DHPG, blue; control, black). Times after application of DHPG are indicated in minutes. (B) Summary of the time course of effects of DHPG on currents in CA1 pyramidal neurons. Paired t test at t = 15 min, ** p<0.001 versus t = 0 min for steps to 0 mV and p = 0.63 for steps to −40 mV. Interval between trials is 20 s. (C) Voltage-clamped Ba2+ currents (steps from −90 to 0 mV) in oocytes expressing mGluR5 together with either Cav2.3 (5 µM DHPG, red; control, black) or Cav3.2. (5 µM DHPG, blue; control, black). (D) Summary of the time course of effects of DHPG on Ba2+ currents in oocytes. Interval between trials is 20 s. DHPG enhances currents in oocytes expressing Cav2.3, but not Cav3.2. Paired t test at t = 15 min, * p<0.01 versus t = 0 min for Cav2.3 and p = 0.27 for Cav3.2.
	Figure 10. Activity dependence of the post-burst medium ADP in the presence of DHPG.(A) Responses to pairs of bursts delivered at different intervals after 20 min application DHPG (2.5 µM). Stimulus for each burst is three brief current stimuli (2 nA, 2 ms). (B) Plot of amplitude of the second medium ADP to the first medium ADP (blue) or the amplitude of the third medium ADP to the first medium ADP (red) as a function of the interval between the two bursts. The medium ADP amplitude was measured at 28 ms after last spike in each burst. (C) Response for the three-burst experiment, where the interval between the first and second burst was 0.1 s and the interval between the second and third burst was 0.5 s (corresponding to the point at 0.6 s in B).

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