Acutely increasing δGABAA receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus

Abstract

Extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that contain the δ subunit (δGABAA receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABAA receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABAA receptor–preferring agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) enhances discrimination memory and increases neurogenesis in the DG. Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABAA receptor activity on memory behaviors remain unknown. Here, we studied the effects of THIP (4 mg/kg, i.p.) on memory performance in wild-type (WT) and δGABAA receptor null mutant (Gabrd−/−) mice. Additionally, the effects of THIP on long-term potentiation (LTP), a molecular correlate of memory, were studied within the DG and CA1 subfields of the hippocampus using electrophysiological recordings of field potentials in hippocampal slices. The results showed that THIP impaired performance in the Morris water maze, contextual fear conditioning and object recognition tasks in WT mice but not Gabrd−/− mice. Furthermore, THIP inhibited LTP in hippocampal slices from WT but not Gabrd−/− mice, an effect that was blocked by GABAA receptor antagonist bicuculline. Thus, acutely increasing δGABAA receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABAA receptor activity.

Neurosteroid effects at α4βδ GABA A receptors alter spatial learning and synaptic plasticity in CA1 hippocampus across the estrous cycle of the mouse

“…This has been shown with a GABA agonist, gaboxadol (Whissell et al, 2013a), at a dose selective for α4βδ GABARs (Brown et al, 2002), as well as for amnestic, sedative drugs such as propofol, isoflurane and benzodiazepines (del Cerro et al, 1992; Nagashima et al, 2005; Saab et al, 2010) although long-term activation of α4βδ GABARs in dentate gyrus improves memory via an effect on neurogenesis (Whissell et al, 2013b). Knock-out of either α4 or δ subunits has also been shown to improve contextual-dependent fear conditioning (Moore et al, 2010; Wiltgen et al, 2005) although sex differences were observed in which trace conditioning or delay conditioning were selectively affected, in female versus male mice, respectively (Moore et al, 2010).…”

Acute pentobarbital treatment impairs spatial learning and memory and hippocampal long-term potentiation in rats

“…Indeed, acute increases in δGABA A receptor activity impair memory and inhibit LTP in the hippocampus [20]. Moreover, the blockade of GABA A receptors facilitates the induction of LTP [21] and rescues propofol-mediated impairment of LTP in the hippocampus [16].…”

Role of α4-containing GABAA receptors in limiting synaptic plasticity and spatial learning of female mice during the pubertal period

“…It is well known that reducing GABA inhibition facilitates synaptic plasticity (Paulsen and Moser, 1998; Wigstrom and Gustafsson, 1983), while GABA agonists impair LTP (Whissell et al, 2013): Positive GABA modulators which enhance GABA inhibition, including benzodiazepines and anesthetics, are known to be amnestic in humans (Veselis et al, 2009). These drugs, and others such as alcohol, impair hippocampal synaptic plasticity and spatial learning in rodents (del Cerro et al, 1992; Izumi et al, 2005; Matthews et al, 2002; Nagashima et al, 2005; Saab et al, 2010).…”

“…Knock-out of either α4 or δ subunits has also been shown to improve this type of learning (Moore et al, 2010; Wiltgen et al, 2005) although sex differences were observed in which trace conditioning or delay conditioning were selectively affected, in female versus male mice, respectively (Moore et al, 2010). Other studies have shown that acute administration of gaboxadol, to activate δ-containing GABARs, impairs both LTP and spatial learning in the hippocampus (Whissell et al, 2013). …”