Skip to main content

Advertisement

Muscarynic metabotropic receptor M4 modulates the hippocampal CA1 LTP possibly through local GABAergic interneurons

Article metrics

  • 745 Accesses

Muscarinic Cholinergic receptors of the subtype M4 are G protein coupled receptors that activate Gi reducing AMPc concentration on the cell and closing K+ channels, causing hyperpolarization of the cell membrane and reduction of neurotransmitter release [1]. Previous works from our laboratory using the very selective Muscarinic Toxin 3 (MT3) to block M4 receptors showed that infusion of this substance into the dorsal hippocampus impairs memory consolidation [2] and facilitates memory retrieval [3], suggesting an important role for M4 modulation of CA1 circuitry in memory processes. Also, local application of this toxin in hippocampal slices was able to impair long-term potentiation (LTP) [4]. One hypothesis raised to explain these findings suggests that plastic changes taking place in the CA1 circuitry involves differential control of local excitatory cells and inhibitory interneurons. Since changes in LTP can be elicited by different mechanisms, the objective of this work was to verify, through an analog of the pharmacological infusion used in the behavioral studies, the effect of MT3 on LTP and the activity of inhibitory interneurons as possible targets of this cholinergic action.

Thus, we recorded fEPSP from Schaffer collaterals at hippocampal CA1 area of rats anesthetized under urethane. After setting the position and the stimulation intensity to obtain 50% of maximum fEPSP, we recorded 10 min baseline followed by drug infusion (0.5μl, 20μl/h) through a delicate cannula glued to the recording electrode at the contralateral side of stimulae. We infused either MT3 (2.0μg), baclofen (0.1μg), MT3+baclofen (same doses), or their vehicles. After 15min, we applied a high frequency stimulation (HFS) protocol (10 trains at 0.5Hz of 20 pulses 100Hz) and recorded the fEPSP for at least 90min. None of the treatments affected the baseline excitability.

Our results indicate that: MT3 infusion 15min before HFS was able to block LTP, consistent with our previous finding with MT3 applied 2min before HFS [4], and baclofen, a GABAB receptor agonist in a subeffective dose, was able to prevent this MT3 effect. Considering that hippocampal GABAB receptors are mainly presynaptic and mostly located in GABAergic interneurons, and that its activation leads to cell hyperpolarization / reduction of GABA release, our results suggest that the M4 receptors relevant to those behavioral responses may be colocalized with GABAB receptors in the CA1 interneurons. Further studies are necessary to verify this hypothesis.

References

  1. 1.

    Sánchez G, Colettis N, Vázquez P, Cerveñansky C, Aguirre A, Quillfeldt JA, Jerusalinsky D, Kornisiuk E: Muscarinic inhibition of hippocampal and striatal adenylyl cyclase is mainly due to the M(4) receptor. Neurochem Res. 2009, 34 (8): 1363-1371. 10.1007/s11064-009-9916-9.

  2. 2.

    Ferreira AR, Fürstenau L, Blanco C, Kornisiuk E, Sánchez G, Daroit D, Castro eSilva M, Cerveñansky C, Jerusalinsky D, Quillfeldt JA: Role of hippocampal M1 and M4 muscarinic receptor subtypes in memory consolidation in the rat. Pharmacol Biochem Behav. 2003, 74 (2): 411-415. 10.1016/S0091-3057(02)01007-9.

  3. 3.

    Diehl F, Fürstenau de Oliveira L, Sánchez G, Camboim C, de Oliveira Alvares L, Lanziotti VB, Cerveñansky C, Kornisiuk E, Jerusalinky D, Quillfeldt JA: Facilitatory effect of the intra-hippocampal pre-test administration of MT3 in the inhibitory avoidance task. Behav Brain Res. 2007, 177 (2): 227-231. 10.1016/j.bbr.2006.11.030.

  4. 4.

    Sanchez Gonzalo, de Oliveira Alvares Lucas, Oberholzer Maria Victoria, Genro Bruna, Quillfeldt Jorge, Costa da Costa Jaderson, Cerveñansky Carlos, Jerusalinsky Diana, Kornisiuk Edgar: M4 Muscarinic Receptors Are Involved in Modulation of Neurotransmission at Synapses of Schaffer Collaterals on CA1. Journal of Neuroscience Research. 2009, 87: 691-700. 10.1002/jnr.21876.

Download references

Author information

Correspondence to Querusche K Zanona.

Rights and permissions

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zanona, Q.K., Boos, F.Z., Crestani, A.P. et al. Muscarynic metabotropic receptor M4 modulates the hippocampal CA1 LTP possibly through local GABAergic interneurons. BMC Neurosci 15, P63 (2014) doi:10.1186/1471-2202-15-S1-P63

Download citation

Keywords

  • Baclofen
  • GABAB Receptor
  • Inhibitory Interneuron
  • GABAergic Interneuron
  • High Frequency Stimulation