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Acutely increasing δGABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus.

Whissell PD, Eng D, Lecker I, Martin LJ, Wang DS, Orser BA - Front Neural Circuits (2013)

Bottom Line: Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABA(A) receptor activity on memory behaviors remain unknown.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.These results have important implications for the development of therapies aimed at increasing δGABA(A) receptor activity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, University of Toronto Toronto, ON, Canada.

ABSTRACT
Extrasynaptic γ-aminobutyric acid type A (GABA(A)) receptors that contain the δ subunit (δGABA(A) receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABA(A) receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABA(A) 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 δGABA(A) 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 δGABA(A) receptor 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 GABA(A) receptor antagonist bicuculline. Thus, acutely increasing δGABA(A) receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABA(A) receptor activity.

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Related in: MedlinePlus

THIP impairs novel object recognition. (A) Schematic diagram showing the protocol. (B) THIP decreased the preference for the novel object in WT but not Gabrd−/− mice. (C) THIP had no effect on total interaction time in both WT and Gabrd−/− mice. n = 12–21, *p < 0.05.
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Figure 3: THIP impairs novel object recognition. (A) Schematic diagram showing the protocol. (B) THIP decreased the preference for the novel object in WT but not Gabrd−/− mice. (C) THIP had no effect on total interaction time in both WT and Gabrd−/− mice. n = 12–21, *p < 0.05.

Mentions: This assay was used to study short-term working memory. Twenty-four hours before testing, each mouse was habituated for 15 min in a chamber (20 × 20 × 20 cm) marked with visual cues (Saab et al., 2009). During testing, the mouse was exposed to a set of three identical objects in the chamber for 2 min (Figure 3A). The mouse was then removed from the chamber for 2 min while the entire setup was cleaned with 70% ethanol and one of the objects was replaced with a novel object (NO). The mouse was then returned to the chamber and the interaction time with the two familiar objects (O1 + O2) and the NO was recorded. Total interaction time was the sum of these interaction times (O1 + O2 + NO). NO preference (%) was defined as NO/(O1 + O2 + NO) × 100. An interaction was defined as active investigation of the object while the mouse was within 1 cm of the object and oriented toward it. Mice with a total interaction time of less than 3 s were excluded from analysis.


Acutely increasing δGABA(A) receptor activity impairs memory and inhibits synaptic plasticity in the hippocampus.

Whissell PD, Eng D, Lecker I, Martin LJ, Wang DS, Orser BA - Front Neural Circuits (2013)

THIP impairs novel object recognition. (A) Schematic diagram showing the protocol. (B) THIP decreased the preference for the novel object in WT but not Gabrd−/− mice. (C) THIP had no effect on total interaction time in both WT and Gabrd−/− mice. n = 12–21, *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3775149&req=5

Figure 3: THIP impairs novel object recognition. (A) Schematic diagram showing the protocol. (B) THIP decreased the preference for the novel object in WT but not Gabrd−/− mice. (C) THIP had no effect on total interaction time in both WT and Gabrd−/− mice. n = 12–21, *p < 0.05.
Mentions: This assay was used to study short-term working memory. Twenty-four hours before testing, each mouse was habituated for 15 min in a chamber (20 × 20 × 20 cm) marked with visual cues (Saab et al., 2009). During testing, the mouse was exposed to a set of three identical objects in the chamber for 2 min (Figure 3A). The mouse was then removed from the chamber for 2 min while the entire setup was cleaned with 70% ethanol and one of the objects was replaced with a novel object (NO). The mouse was then returned to the chamber and the interaction time with the two familiar objects (O1 + O2) and the NO was recorded. Total interaction time was the sum of these interaction times (O1 + O2 + NO). NO preference (%) was defined as NO/(O1 + O2 + NO) × 100. An interaction was defined as active investigation of the object while the mouse was within 1 cm of the object and oriented toward it. Mice with a total interaction time of less than 3 s were excluded from analysis.

Bottom Line: Despite the potential therapeutic benefits of such treatments, the effects of acutely increasing δGABA(A) receptor activity on memory behaviors remain unknown.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.These results have important implications for the development of therapies aimed at increasing δGABA(A) receptor activity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Medical Science, University of Toronto Toronto, ON, Canada.

ABSTRACT
Extrasynaptic γ-aminobutyric acid type A (GABA(A)) receptors that contain the δ subunit (δGABA(A) receptors) are expressed in several brain regions including the dentate gyrus (DG) and CA1 subfields of the hippocampus. Drugs that increase δGABA(A) receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. Also, long-term pretreatment with the δGABA(A) 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 δGABA(A) 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 δGABA(A) receptor 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 GABA(A) receptor antagonist bicuculline. Thus, acutely increasing δGABA(A) receptor activity impairs memory behaviors and inhibits synaptic plasticity. These results have important implications for the development of therapies aimed at increasing δGABA(A) receptor activity.

Show MeSH
Related in: MedlinePlus