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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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SR-95531 does not prevent THIP-mediated depression of long-term potentiation in the dentate gyrus. (A,B) THIP impairs LTP in the DG of SR-95531-treated slices from WT but not Gabrd−/− mice. SR-95531 (1 μM) was perfused throughout the recordings. Upper panels: Representative traces before and after tetanic stimulation. Middle panels: Normalized slope of fPSPs following tetanic stimulation. Bottom panels: Summarized data showing the last 5 min of recording. n = 10–12. *p < 0.05.
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Figure 7: SR-95531 does not prevent THIP-mediated depression of long-term potentiation in the dentate gyrus. (A,B) THIP impairs LTP in the DG of SR-95531-treated slices from WT but not Gabrd−/− mice. SR-95531 (1 μM) was perfused throughout the recordings. Upper panels: Representative traces before and after tetanic stimulation. Middle panels: Normalized slope of fPSPs following tetanic stimulation. Bottom panels: Summarized data showing the last 5 min of recording. n = 10–12. *p < 0.05.

Mentions: Next, LTP was studied in the presence of SR-95531 (1 μM), a compound that preferentially blocks synaptic GABAA receptors at low concentrations (Nusser and Mody, 2002). Application of SR-95531 alone did not significantly elevate LTP (WT = 112.2 ± 6.7% vs. WT + SR-95531 = 123.3 ± 5.2%, Gabrd−/− = 110.0 ± 6.5% vs. Gabrd−/− + SR-95531 = 125.7 ± 5.4%; p > 0.05, n = 10–12) (Figures 5, 7). THIP reduced LTP in SR-95531-treated slices from WT mice (Figure 7; WT + SR-95531 = 123.3 ± 5.2% and WT + SR-95531 + THIP = 107.8 ± 7.2%, drug effect, p < 0.05, n = 10–12), but not in slices from Gabrd−/− mice (Figure 7; Gabrd−/− + SR-95531 = 125.7 ± 5.4%, Gabrd−/− + SR-95531 + THIP = 124.4 ± 5.2%; drug effect, p > 0.05, n = 10–12). These results indicate that the inhibitory effects of THIP on LTP are mediated by extrasynaptic rather than synaptic GABAA receptors.


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)

SR-95531 does not prevent THIP-mediated depression of long-term potentiation in the dentate gyrus. (A,B) THIP impairs LTP in the DG of SR-95531-treated slices from WT but not Gabrd−/− mice. SR-95531 (1 μM) was perfused throughout the recordings. Upper panels: Representative traces before and after tetanic stimulation. Middle panels: Normalized slope of fPSPs following tetanic stimulation. Bottom panels: Summarized data showing the last 5 min of recording. n = 10–12. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: SR-95531 does not prevent THIP-mediated depression of long-term potentiation in the dentate gyrus. (A,B) THIP impairs LTP in the DG of SR-95531-treated slices from WT but not Gabrd−/− mice. SR-95531 (1 μM) was perfused throughout the recordings. Upper panels: Representative traces before and after tetanic stimulation. Middle panels: Normalized slope of fPSPs following tetanic stimulation. Bottom panels: Summarized data showing the last 5 min of recording. n = 10–12. *p < 0.05.
Mentions: Next, LTP was studied in the presence of SR-95531 (1 μM), a compound that preferentially blocks synaptic GABAA receptors at low concentrations (Nusser and Mody, 2002). Application of SR-95531 alone did not significantly elevate LTP (WT = 112.2 ± 6.7% vs. WT + SR-95531 = 123.3 ± 5.2%, Gabrd−/− = 110.0 ± 6.5% vs. Gabrd−/− + SR-95531 = 125.7 ± 5.4%; p > 0.05, n = 10–12) (Figures 5, 7). THIP reduced LTP in SR-95531-treated slices from WT mice (Figure 7; WT + SR-95531 = 123.3 ± 5.2% and WT + SR-95531 + THIP = 107.8 ± 7.2%, drug effect, p < 0.05, n = 10–12), but not in slices from Gabrd−/− mice (Figure 7; Gabrd−/− + SR-95531 = 125.7 ± 5.4%, Gabrd−/− + SR-95531 + THIP = 124.4 ± 5.2%; drug effect, p > 0.05, n = 10–12). These results indicate that the inhibitory effects of THIP on LTP are mediated by extrasynaptic rather than synaptic GABAA receptors.

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