Trace fear conditioning involves hippocampal α ₅ GABA _A receptors

Abstract

The heterogeneity of ␥-aminobutyric acid type A (GABAA) receptors contributes to the diversity of neuronal inhibition in the regulation of information processing. Although most GABA A receptors are located synaptically, the small population of ␣5GABAA receptors is largely expressed extrasynaptically. To clarify the role of the ␣5GABAA receptors in the control of behavior, a histidineto-arginine point mutation was introduced in position 105 of the murine ␣5 subunit gene, which rendered the ␣5GABAA receptors diazepam-insensitive. Apart from an incomplete muscle relaxing effect, neither the sedative, anticonvulsant, nor anxiolytic-like activity of diazepam was impaired in ␣5(H105R) mice. However, in hippocampal pyramidal cells, the point mutation resulted in a selective reduction of ␣5GABAA receptors, which altered the drugindependent behavior. In line with the role of the hippocampus in certain forms of associative learning, trace fear conditioning, but not delay conditioning or contextual conditioning, was facilitated in the mutant mice. Trace fear conditioning differs from delay conditioning in that the conditioned and unconditioned stimulus are separated by a time interval. Thus, the largely extrasynaptic ␣5GABAA receptors in hippocampal pyramidal cells are implicated as control elements of the temporal association of threat cues in trace fear conditioning.

Are GABAA Receptors Containing α5 Subunits Contributing to the Sedative Properties of Benzodiazepine Site Agonists?

“…Evidently, all three newly synthesized BZ site ligands could have acted through the a 5 subtype-containing GABA A receptors, one of them (SH-053-R-CH3) as an essentially subtype-selective ligand. There exist data that support the possibility of substantial motor manifestations of a5-containing GABA A receptor modulation, besides the indirect consequences brought on by the effects on learning and memory processes, where pertinent (Collinson et al, 2002;Crestani et al, 2002). Somatic and preganglionic motoneurons in the spinal cord exhibit a moderate-to-strong staining for the a5 subunit (Bohlhalter et al, 1996), whereas the knock-in mice harboring the a5 subunit insensitive to diazepam are refractory to development of tolerance to the sedative effect of diazepam dosed subchronically, presumably due to a downregulation of a5 subunits in the dentate gyrus (van Rijnsoever et al, 2004).…”

“…Knock-in mice with the GABA A receptor a5 subunit rendered insensitive to diazepam were refractory to development of tolerance to the sedative effect of diazepam dosed subchronically (van Rijnsoever et al, 2004). These two sets of evidence indicate that the motor influence of a5-GABA A receptor modulation, if present, is not necessarily an indirect consequence of the established effects on learning and memory processes (Collinson et al, 2002;Crestani et al, 2002). Hence, any activity changes seen with ligands possessing a substantial agonistic efficacy for a5 subunit containing GABA A receptors may be, at least partly, mediated by such receptors.…”

A functional polymorphism in the succinate-semialdehyde dehydrogenase (aldehyde dehydrogenase 5 family, member A1) gene is associated with cognitive ability

“…[23][24][25][26] Even in the absence of neurotoxicity, GABA is therefore well placed to contribute to information processing, memory acquisition, learning and other cognitive processes. 27 Interestingly, the learning deficits in an animal model of neurofibromatosis type I have recently been attributed to deficits in LTP, resulting from increased GABA-mediated inhibition. 28 Moreover, as the LTP and learning deficits were reversed by GABA antagonist, the impairment is not likely to be attributable to neurotoxicity.…”

A schizophrenia-related sensorimotor deficit links α3-containing GABA A receptors to a dopamine hyperfunction

“…Because the anxiolytic-like activity of diazepam in the elevatedplus-maze test is mediated by ␣2-containing GABA A receptors (26), but apparently not by ␣1-, ␣3-and ␣5-containing GABA A receptors (26)(27)(28)(29), this drug action was expected to remain undisturbed in the ␣3KO mice. As illustrated in Fig.…”