Cellular correlates of anxiety in CA1 hippocampal pyramidal cells of 5-HT1A receptor knockout mice.
BACKGROUND
5-HT(1A) receptor knockout (1AKO) mice have a robust anxiety phenotype. Tissue-specific "rescue" strategies and electrophysiology have implicated a critical role for postsynaptic 5-HT(1A) receptors, particularly in the CA1 region of the hippocampus.


OBJECTIVE
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-HT(1A) receptor. These data provide new information about interactions between 5-HT, GABA, and glutamate systems during the expression of chronic anxiety.
Freeman-Daniels
Emily
E
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Beck
Sheryl G
SG
Kirby
Lynn G
LG
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology*; D002243:Carbolines / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D014151:Anti-Anxiety Agents; D002243:Carbolines; D044282:Receptor, Serotonin, 5-HT1A; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C035874:FG 7142; D003975:Diazepam