Trace fear conditioning is enhanced in mice lacking the δ subunit of the GABAA receptor

By B. Wiltgen, M. J. Sanders, C. Ferguson, G. Homanics, M. Fanselow. 2005

94 citations recorded by the source corpus.

In the central nervous system, fast inhibitory transmission is mediated primarily by γ-aminobutyric acid type A receptors (GABAARs) (Macdonald and Olsen 1994; Olsen and Homanics 2000). These ligand-gated receptors are pentamers composed of various subunit combinations (α, β, γ, e, π, ρ, and δ) that exhibit differential expression in the brain (Barnard et al. 1998; Sieghart and Sperk 2002). For example, the δ subunit is highly expressed in the dentate gyrus, but not CA3 or CA1 regions of the hippocampus (Persohn et al. 1992; Peng et al. 2002). The pharmacologic and kinetic properties of GABAARs are highly dependent on the specific configuration of these subunits (Quirk et al. 1994; Gunther et al. 1995; Smith and Olsen 1995; Khan et al. 1996; Benke et al. 1997). Recent studies have shown that genetic deletion of the δ subunit of the GABAAR produces a significant reduction in neurosteroid sensitivity (Mihalek et al. 1999; Vicini et al. 2002; Porcello et al. 2003; Spigelman et al. 2003) and accelerates the decay of spontaneous mIPSCs and evoked IPSPs in hippocampal granule cells and thalamic relay neurons (Mihalek et al. 1999; Porcello et al. 2003; Spigelman et al. 2003). These data suggest that δ-containing GABAARs contribute to synaptic and extrasynaptic inhibition and facilitate modulation by neuroactive steroids. Pharmacologic or genetic manipulations that reduce GABAergic inhibition often enhance synaptic plasticity and learning (Introini-Collison et al. 1994; Crestani et al. 1999, 2002; Staubli et al. 1999; Shumyatsky et al. 2002). For example, recent experiments on GABAAR mutants (α5 and γ2) found enhanced trace but normal delay conditioning (Crestani et al. 1999, 2002). Trace conditioning is a form of hippocampus-dependent learning in which the conditional stimulus (CS) and unconditional stimulus (US) are separated in time (Solomon et al. 1986; Moyer Jr. et al. 1990; McEchron et al. 1998; Huerta et al. 2000; Quinn et al. 2002). This is distinct from hippocampus-independent delay conditioning in which the CS and US are presented contiguously. Previous work has demonstrated that trace conditioning engages the CA1 region of the hippocampus (Moyer Jr. et al. 1996, 2000; McEchron and Disterhoft 1999; McEchron et al. 2001, 2003; Leuner et al. 2003) and requires NMDAR-dependent plasticity in this region (Huerta et al. 2000). Relatively little is known about the contribution of the dentate gyrus to trace conditioning, although recent studies suggest this region also plays an important role. For example, exposure to a trace-conditioned cue produces significant increases in immediate early gene expression in the dentate gyrus (Weitemier and Ryabinin 2004). Trace conditioning also increases neurogenesis in the dentate gyrus (Gould et al. 1999) and is impaired by a reduction in the number of newly generated neurons in this region (Shors et al. 2001). The current experiments used δ knockout (KO) mice to examine the effects of reduced inhibition and neurosteroid sensitivity in the dentate gyrus on the acquisition of trace fear conditioning. We also looked for nonspecific effects of δ subunit deletion by examining performance on open-field and RotaRod tests.

Subfields: Behavioral Neuroscience, Cellular and Molecular Neuroscience, Neurology

View Paper: https://www.semanticscholar.org/paper/48735d2f4f26ab38f9f416da06f0b152f1ce4ecf

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

  1. U. Rudolph

Citations in the corpus