Elsevier

Neuroscience

Volume 151, Issue 1, 2 January 2008, Pages 209-221
Neuroscience

Neuropharmacology
Layer selective presynaptic modulation of excitatory inputs to hippocampal cornu Ammon 1 by μ-opioid receptor activation

https://doi.org/10.1016/j.neuroscience.2007.09.077Get rights and content

Abstract

Chronic and acute activation of μ-opioid receptors (MOR) in hippocampal cornu Ammon 1 (CA1) disrupts rhythmic activity, alters activity-dependent synaptic plasticity and impairs spatial memory formation. In CA1, MORs act by hyperpolarizing inhibitory interneurons and suppressing inhibitory synaptic transmission. MOR modulation of inhibitory synaptic function translates into an increase in excitatory activity in all layers of CA1. However, the exact anatomical sites for MOR actions are not completely known. Therefore, we used voltage-sensitive dye imaging, whole cell patch clamping, photolysis of α-carboxy-2-nitrobenzyl ester, trifluoroacetic acid salt (CNB) –caged GABA, and micro-sectioned slices of rat hippocampus to investigate the effect of MOR activation in CA1. First, we investigated the effect of MOR activation using a MOR agonist [d-Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO) on the direct activation of GABA receptors by photolysis of CNB-caged GABA in all layers of CA1. MOR activation did not affect hyperpolarizations due to direct GABA receptor activation in any layer of CA1, but MOR activation did suppress GABAergic inhibitory postsynaptic potentials suggesting that MOR activation acts by presynaptically inhibiting interneuron function. We next examined whether MOR activation was equivalently effective in all anatomical layers of CA1. To do this, cuts were made between anatomical layers of CA1 and isolated layers were stimulated electrically (five pulses at 20 Hz) to produce excitatory postsynaptic potentials (EPSPs). Under these conditions, MOR activation significantly increased EPSP areas in stratum radiatum (SR), stratum pyramidale (SP) and stratum oriens (SO) relative to stratum lacunosum-moleculare (SLM). When compared with the effect of GABAA and GABAB receptor antagonists on EPSP areas, the effect of DAMGO was proportionately larger in SR, SP and SO than in SLM. We conclude that MOR activation is more effective at directly modulating activity in SR, SP and SO, and the smaller effect in SLM is likely due to a smaller MOR inhibition of GABA release in SLM.

Section snippets

Preparation of hippocampal slices and staining with VSD

Use of animals in this study was approved by the Virginia Commonwealth University Institutional Animal Care and Use Committee and adhered to U.S. federal guidelines of the Animal Welfare Act and Animals Welfare Regulations and the Public Health Service Policy on Humane Care of Use of Laboratory Animals. The number of animals used in this study was limited to those necessary to show statistical differences and animals were never exposed to pain or suffering. Specifically, male Sprague–Dawley

Results

Previous studies have suggested that MOR activation can influence excitatory activity in all layers of hippocampal CA1 (McQuiston and Saggau 2003, McQuiston 2007). However, the relative effectiveness of MOR activation in the discrete layers of CA1 is not fully understood. Therefore, we performed the following experiments in an effort to determine the effect of MOR activation on excitatory activity in each anatomical layer of CA1 and to determine the synaptic location of MOR activation. First,

Discussion

This study has shown that MOR activation has direct effects in all layers of hippocampal CA1. Furthermore, the effect of MOR activation was presynaptic on inhibitory interneurons because the VSD response to direct application of GABA in all layers of CA1 was not affected by MOR activation, whereas IPSPs were suppressed by DAMGO. However, not all layers were equally affected. MOR activation had a smaller effect on EPSPs in SLM compared with all other layers. Furthermore, when comparing the

Conclusion

In conclusion, MOR activation in hippocampal CA1 had a significantly larger impact on excitatory activity in SR, SO and SP relative to SLM. These data suggest that MORs will have significant influences on inputs from CA3 pyramidal cells in SR and SO and will also facilitate firing of action potentials in pyramidal cell bodies. In contrast, MOR activation had a small effect on excitatory activity in SLM. These data point to modulation of inputs from CA3 and the output of CA1 pyramidal neurons as

Acknowledgments

The author would like to thank Karen A. Bell for her comments on this manuscript. This work was supported by a grant from NIDA R01-DA017110.

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