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. 2008 Sep;28(6):1116-26.
doi: 10.1111/j.1460-9568.2008.06409.x. Epub 2008 Sep 9.

mGluR-dependent persistent firing in entorhinal cortex layer III neurons

Motoharu Yoshida  1 , Erik Fransén, Michael E Hasselmo
Affiliations

mGluR-dependent persistent firing in entorhinal cortex layer III neurons

Motoharu Yoshida et al. Eur J Neurosci. 2008 Sep.

Abstract

Persistent firing is believed to be a crucial mechanism for memory function including working memory. Recent in vivo and in vitro findings suggest an involvement of metabotropic glutamate receptors (mGluRs) in persistent firing. Using whole-cell patch-recording techniques in a rat entorhinal cortex (EC) slice preparation, we tested whether EC layer III neurons display persistent firing due to mGluR activation, independently of cholinergic activation. Stimulation of the angular bundle drove persistent firing in 90% of the cells in the absence of a cholinergic agonist. The persistent firing was typically stable for > 4.5 min at which point persistent firing was terminated by the experimenter. The average frequency of the persistent firing was 2.1 Hz, ranging from 0.4 to 5.5 Hz. This persistent firing was observed even in the presence of atropine (2 microM), suggesting that the persistent firing can occur independent of cholinergic activation. Furthermore, ionotropic glutamate and GABAergic synaptic blockers (2 mM kynurenic acid, 100 microM picrotoxin and 1 microM CGP55845) did not block the persistent firing. On the other hand, blockers of group I mGluRs (100 microM LY367385 and 20 microM MPEP) completely blocked or suppressed the persistent firing. An agonist of group I mGluRs (20 microM DHPG) greatly enhanced the persistent firing induced by current injection. These results indicate that persistent firing can be driven through group I mGluRs in entorhinal layer III neurons, suggesting that glutamatergic synaptic input alone could enable postsynaptic neurons to hold input signals in the form of persistent firing.

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Figures

Fig. 1
Fig. 1
Persistent firing in a physiological condition without cholinergic agonist. (a) Stimulation of the angular bundle (20 Hz, 2s) caused stable persistent firing. Bottom trace shows timing of stimulation. (b) Frequency of the persistent firing in (a). (c) Magnification of membrane potential trace during stimulation in (a). (d) Higher magnification of initial part of the stimulation in (c). A: stimulus artifact, E: EPSP, S: spike.
Fig. 2
Fig. 2
Persistent firing with cholinergic receptor antagonist and synaptic blockers. (a) Left: An example of persistent firing in cholinergic antagonist atropine (2 μM). Right: Magnification of trace during stimulation. (b) An example of persistent firing in ionotropic glutamate synaptic blocker and GABAergic synaptic blockers (2 mM kynurenic acid, 100 μM picrotoxin and 1 μM CGP55845) as well as atropine. (c) Response to single pulse synaptic stimulation. Atro: atropine. SB: synaptic blockers. (d) Frequency of persistent firing in normal ACSF (shown in Fig. 1), atropine, and atropine + synaptic blockers. (e) Efficiency of one spike. (f) Membrane potential during synaptic stimulation. (g) Number of spikes during synaptic stimulation. ns: not significant.
Fig. 3
Fig. 3
Effect of mGluR blockers on persistent firing induced by synaptic stimulation. (a) – (c) Persistent activity in a representative cell in (a) control (with atropine, ionotropic glutamate synaptic blockers and GABAergic synaptic blockers), (b) group I mGluR blockers and (c) after wash out of the group I mGluR blockers. (d) Frequency of persistent firing. (e) Efficiency of one spike to cause persistent firing. (f) Membrane potential during stimulation. (g) Number of spikes during stimulation. Note significant decrease in the frequency of persistent firing and the efficiency of one spike. Significances from Tukey post-hoc test are shown. *: 0.01 ≤ P < 0.05, **: 0.001 ≤ P < 0.01, ***: P < 0.001. Differences between pairs without asterisks were not significant.
Fig. 4
Fig. 4
Comparison of persistent firing induced by synaptic stimulation and current injection. (a) Persistent firing induced by synaptic stimulation. (b) Magnification of trace during stimulation in (a). (c) Persistent firing induced by current injection in the same cell as in (a). (d) Magnification of trace during stimulation in (c). (e) Frequency of persistent firing (white = synaptic stimulation, black = current injection). (f) Efficiency of one spike. (g) Membrane potential during stimulation. (h) Number of spikes induced during stimulation. *: 0.01 ≤ P < 0.05.
Fig. 5
Fig. 5
Effect of group I mGluR blockers on persistent firing induced by current injection. (a) - (c) Persistent activity in (a) control (with atropine, ionotropic glutamate synaptic blockers and GABAergic synaptic blockers), (b) group I mGluR blockers and (c) after wash out of the group I mGluR blockers. (d) Frequency of persistent firing. (e) Efficiency of one spike to cause persistent firing. (f) Membrane potential during stimulation. (g) Number of spikes during stimulation. Significances from Tukey post-hoc test are shown. *: 0.01 ≤ P < 0.05. Differences between pairs without asterisks were not significant.
Fig. 6
Fig. 6
Effect of group I mGluR agonist on persistent firing induced by current injection. (a) Persistent firing induced by current injection to the soma in normal ACSF. (b) Persistent firing induced by current injection to the soma in DHPG (5 μM). (c) Frequency of persistent firing (white = normal ACSF, black = DHPG). (d) Efficiency of one spike. (e) Membrane potential during stimulation. (f) Number of spikes during stimulation. **: 0.001 ≤ P < 0.01, ***: P < 0.001.
Fig. 7
Fig. 7
Graded persistent firing induced by synaptic stimulation in cholinergic muscarinic receptor antagonist. (a) An example of graded persistent firing in the presence of atropine. (b) Change in firing frequency of persistent firing as the function of number of repeated stimulation pulses. Numbers on top of the bar graphs show number of cells.
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