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Cellular correlates of anxiety in CA1 hippocampal pyramidal cells of 5-HT1A receptor knockout mice

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Abstract

Rationale

5-HT1A receptor knockout (1AKO) mice have a robust anxiety phenotype. Tissue-specific “rescue” strategies and electrophysiology have implicated a critical role for postsynaptic 5-HT1A receptors, particularly in the CA1 region of the hippocampus.

Objectives

In this study, we evaluated differences in membrane properties and synaptic activity in CA1 hippocampal pyramidal cells between 1AKOs and wild-type (WT) controls to better understand the cellular correlates of anxiety in this mouse model.

Methods

Whole-cell patch-clamp recordings were conducted in CA1 pyramidal cells in hippocampal brain slices from 1AKOs and WTs that had previously been screened for anxiety with the elevated-plus maze. Spontaneous miniature inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs) and stimulus-evoked eIPSCs and eEPSCs were recorded in addition to the effect of the benzodiazepine agonist diazepam or the inverse agonist FG 7142 on γ-aminobutyric acid (GABA)ergic eIPSCs.

Results

Evoked EPSC amplitude was greater in 1AKOs than WTs. When subjects were pooled across genotypes, anxiety measures correlated with eEPSC amplitude, indicating enhanced postsynaptic glutamate synaptic activity under conditions of synaptic activation in anxious subjects. While GABA synaptic activity and sensitivity to diazepam were not affected by genotype or correlated with anxiety, sensitivity to the anxiogenic FG 7142 was smaller in anxious subjects.

Conclusions

These data indicate enhanced postsynaptic glutamate receptor sensitivity and decreased GABAergic inhibition by a benzodiazepine inverse agonist in CA1 hippocampal neurons of anxious mice are produced by deletion of the 5-HT1A receptor. These data provide new information about interactions between 5-HT, GABA, and glutamate systems during the expression of chronic anxiety.

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Acknowledgments

We thank Drs. Mark Geyer and Victoria Risbrough in the Dept. of Psychiatry at the University of California, San Diego for the generous donation of breeding pairs of 129/Sv 5-HT1A knockout mice and wild-type controls for use in these studies. We thank Alessandra Cathel for her technical assistance and contributions to electrophysiological studies. This work was supported by a Young Investigator Award from the National Association of Research on Schizophrenia and Depression (NARSAD) and a National Institute of Mental Health grant (MH 63301) issued to Dr. Kirby and by National Institute of Mental Health grants (MH 48125 and MH 63078) issued to Dr. Beck.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology and Center for Substance Abuse Research, Temple University School of Medicine, 3500 N. Broad St, Philadelphia, PA, 19140, USA

    Emily Freeman-Daniels & Lynn G. Kirby

  2. Department of Anesthesiology, University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia Research Institute, Philadelphia, PA, USA

    Sheryl G. Beck

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  1. Emily Freeman-Daniels
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  2. Sheryl G. Beck
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  3. Lynn G. Kirby
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Correspondence to Lynn G. Kirby.

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Freeman-Daniels, E., Beck, S.G. & Kirby, L.G. Cellular correlates of anxiety in CA1 hippocampal pyramidal cells of 5-HT1A receptor knockout mice. Psychopharmacology 213, 453–463 (2011). https://doi.org/10.1007/s00213-010-2030-5

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  • DOI: https://doi.org/10.1007/s00213-010-2030-5

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