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Cyclodextrin Alters GABAergic Input to CA1 Pyramidal Cells in Wild-Type But Not in NPC1-Deficient Mice.

Frech MJ, Rabenstein M, Bovensiepen K, Rost S, Rolfs A - Biores Open Access (2015)

Bottom Line: Although the IPSCs were mainly GABAergic, we observed a significant reduction of the IPSC frequency in the presence of the glycine receptor antagonist strychnine.The effect of strychnine did not differ in untreated and treated animals, indicating that the effect of CDX was most likely not based on an interaction with glycinergic transmission machinery.However, the unexpected effect of CDX on the GABAergic synaptic transmission is of special interest as a disturbance plays, for example, a crucial role in epilepsy and, moreover, as CDX is currently under investigation as a treatment for NPC1 in humans.

View Article: PubMed Central - PubMed

Affiliation: Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock , Rostock, Germany .

ABSTRACT
Niemann-Pick type C1 disease (NPC1) is a neurodegenerative disorder caused by mutations in the NPC1 gene. Actual, no causative treatment for NPC1 is available, although some drugs have been proven to be beneficial to patients, for example, 2-hydroxypropyl-β-cyclodextrin (CDX). In this study, we used the BALB/c_Nctr-Npc1m1N/-J mouse strain to study the effect of CDX, which is described to prolong the life span and to alleviate the pathogenic phenotype. By means of patch clamp recordings, we measured inhibitory postsynaptic currents (IPSCs) of CA1 pyramidal cells of CDX-treated and -untreated animals to elucidate the influence of CDX on the synaptic transmission. Surprisingly, CDX induced a significantly higher GABAergic IPSC frequency in wild-type mice than in NPC1(-/-) mice. Although the IPSCs were mainly GABAergic, we observed a significant reduction of the IPSC frequency in the presence of the glycine receptor antagonist strychnine. The effect of strychnine did not differ in untreated and treated animals, indicating that the effect of CDX was most likely not based on an interaction with glycinergic transmission machinery. However, the unexpected effect of CDX on the GABAergic synaptic transmission is of special interest as a disturbance plays, for example, a crucial role in epilepsy and, moreover, as CDX is currently under investigation as a treatment for NPC1 in humans.

No MeSH data available.


Related in: MedlinePlus

(A) IPSCs recorded under control, Stry, and Stry+GBZ. (B) Plot of IPSC amplitudes versus time. IPSCs recorded in the presence of Stry are referred as GABAergic IPSCs, as they were blocked by GBZ. Analysis of frequencies (C) and amplitudes (D) of IPSCs recorded in untreated mice (−CDX) and treated mice (+CDX) revealed significantly higher frequencies in WT mice but not in NPC1−/− mice. CDX, 2-hydroxypropyl-β-cyclodextrin; GBZ, gabazine; IPSCs, inhibitory postsynaptic currents; NPC1, Niemann–Pick type C1 disease; Stry, strychnine; WT, wild type.
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f1: (A) IPSCs recorded under control, Stry, and Stry+GBZ. (B) Plot of IPSC amplitudes versus time. IPSCs recorded in the presence of Stry are referred as GABAergic IPSCs, as they were blocked by GBZ. Analysis of frequencies (C) and amplitudes (D) of IPSCs recorded in untreated mice (−CDX) and treated mice (+CDX) revealed significantly higher frequencies in WT mice but not in NPC1−/− mice. CDX, 2-hydroxypropyl-β-cyclodextrin; GBZ, gabazine; IPSCs, inhibitory postsynaptic currents; NPC1, Niemann–Pick type C1 disease; Stry, strychnine; WT, wild type.

Mentions: In this study, we measured inhibitory postsynaptic currents (IPSCs) of pyramidal cells in the CA1 region of the hippocampus by means of patch clamp recordings. Using a symmetrical Cl− concentration and a holding potential of −60 mV, the activation of Cl−-permeable ion channels like GABAA receptors (GABAA-Rs) or glycine receptors (Gly-Rs) was demonstrated as inward directed currents (Fig. 1A). We used the antagonists gabazine (GBZ; 5 μM) and strychnine (Stry; 1 μM) to antagonize GABAA-Rs- and Gly-Rs-mediated IPSCs. The application of GBZ resulted in a block of the IPSCs (Fig. 1A, B), indicating that the IPSCs were mediated by GABAA-Rs and not by Gly-Rs. Consequently, we did not observe IPSCs in experiments starting with an application of GBZ (data not shown). In the following, IPSCs recorded in the absence of antagonists are referred as control (con) and in the presence of strychnine as GABAergic IPSCs.


Cyclodextrin Alters GABAergic Input to CA1 Pyramidal Cells in Wild-Type But Not in NPC1-Deficient Mice.

Frech MJ, Rabenstein M, Bovensiepen K, Rost S, Rolfs A - Biores Open Access (2015)

(A) IPSCs recorded under control, Stry, and Stry+GBZ. (B) Plot of IPSC amplitudes versus time. IPSCs recorded in the presence of Stry are referred as GABAergic IPSCs, as they were blocked by GBZ. Analysis of frequencies (C) and amplitudes (D) of IPSCs recorded in untreated mice (−CDX) and treated mice (+CDX) revealed significantly higher frequencies in WT mice but not in NPC1−/− mice. CDX, 2-hydroxypropyl-β-cyclodextrin; GBZ, gabazine; IPSCs, inhibitory postsynaptic currents; NPC1, Niemann–Pick type C1 disease; Stry, strychnine; WT, wild type.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556338&req=5

f1: (A) IPSCs recorded under control, Stry, and Stry+GBZ. (B) Plot of IPSC amplitudes versus time. IPSCs recorded in the presence of Stry are referred as GABAergic IPSCs, as they were blocked by GBZ. Analysis of frequencies (C) and amplitudes (D) of IPSCs recorded in untreated mice (−CDX) and treated mice (+CDX) revealed significantly higher frequencies in WT mice but not in NPC1−/− mice. CDX, 2-hydroxypropyl-β-cyclodextrin; GBZ, gabazine; IPSCs, inhibitory postsynaptic currents; NPC1, Niemann–Pick type C1 disease; Stry, strychnine; WT, wild type.
Mentions: In this study, we measured inhibitory postsynaptic currents (IPSCs) of pyramidal cells in the CA1 region of the hippocampus by means of patch clamp recordings. Using a symmetrical Cl− concentration and a holding potential of −60 mV, the activation of Cl−-permeable ion channels like GABAA receptors (GABAA-Rs) or glycine receptors (Gly-Rs) was demonstrated as inward directed currents (Fig. 1A). We used the antagonists gabazine (GBZ; 5 μM) and strychnine (Stry; 1 μM) to antagonize GABAA-Rs- and Gly-Rs-mediated IPSCs. The application of GBZ resulted in a block of the IPSCs (Fig. 1A, B), indicating that the IPSCs were mediated by GABAA-Rs and not by Gly-Rs. Consequently, we did not observe IPSCs in experiments starting with an application of GBZ (data not shown). In the following, IPSCs recorded in the absence of antagonists are referred as control (con) and in the presence of strychnine as GABAergic IPSCs.

Bottom Line: Although the IPSCs were mainly GABAergic, we observed a significant reduction of the IPSC frequency in the presence of the glycine receptor antagonist strychnine.The effect of strychnine did not differ in untreated and treated animals, indicating that the effect of CDX was most likely not based on an interaction with glycinergic transmission machinery.However, the unexpected effect of CDX on the GABAergic synaptic transmission is of special interest as a disturbance plays, for example, a crucial role in epilepsy and, moreover, as CDX is currently under investigation as a treatment for NPC1 in humans.

View Article: PubMed Central - PubMed

Affiliation: Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock , Rostock, Germany .

ABSTRACT
Niemann-Pick type C1 disease (NPC1) is a neurodegenerative disorder caused by mutations in the NPC1 gene. Actual, no causative treatment for NPC1 is available, although some drugs have been proven to be beneficial to patients, for example, 2-hydroxypropyl-β-cyclodextrin (CDX). In this study, we used the BALB/c_Nctr-Npc1m1N/-J mouse strain to study the effect of CDX, which is described to prolong the life span and to alleviate the pathogenic phenotype. By means of patch clamp recordings, we measured inhibitory postsynaptic currents (IPSCs) of CA1 pyramidal cells of CDX-treated and -untreated animals to elucidate the influence of CDX on the synaptic transmission. Surprisingly, CDX induced a significantly higher GABAergic IPSC frequency in wild-type mice than in NPC1(-/-) mice. Although the IPSCs were mainly GABAergic, we observed a significant reduction of the IPSC frequency in the presence of the glycine receptor antagonist strychnine. The effect of strychnine did not differ in untreated and treated animals, indicating that the effect of CDX was most likely not based on an interaction with glycinergic transmission machinery. However, the unexpected effect of CDX on the GABAergic synaptic transmission is of special interest as a disturbance plays, for example, a crucial role in epilepsy and, moreover, as CDX is currently under investigation as a treatment for NPC1 in humans.

No MeSH data available.


Related in: MedlinePlus