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

*, Address correspondence to: Moritz J. Frech, PhD, Albrecht-Kossel-Institute for Neuroregeneration, University of Rostock, Gehlsheimer Straße 20, Rostock 18147, Germany, E-mail: [email protected]

© Moritz J. Frech et al. 2015; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

Introduction

Niemann-Pick type C1 disease (NPC1) is a rare progressive neurodegenerative disease caused by mutations in the NPC1 gene, leading to an impaired lipid transport and an accumulation of cholesterol and gangliosides in the late endosomes and lysosomes. Besides clinical manifestation like hepatosplenomegaly, seizures, dementia, and cerebellar ataxia, a progressive neurological degradation is a striking hallmark of NPC1.¹ Although a variety of morphological alterations of neurons are described,^2,3 the pathogenic mechanisms remain to be elucidated. Cholesterol is essential for a proper synaptic transmission, as receptor clustering depends on cholesterol⁴ as well as fusion and release of synaptic vesicles.^5,6 A disturbance of synaptic transmission and plasticity may be causative for clinical symptoms, and thus, studies in this regard are of special interest. An altered excitatory synaptic transmission was observed in cultured hippocampal neurons from NPC1^-/- mice and in hippocampal slices.^7,8 Thus, we asked if any alterations of inhibitory transmission can be found in the hippocampal CA1 formation of NPC1-deficient mice. Furthermore, we were interested in the effect of 2-hydroxypropyl-β-cyclodextrin (CDX) on the synaptic transmission, which has been proven to be beneficial in NPC1^-/- mice.⁹

Materials and Methods

Preparation of hippocampal slices and patch clamp recordings

Animals of the BALB/c_Nctr-Npc1m1N/-J strain (Jackson Laboratories) and wild-type (WT) animals were weekly injected subcutaneously with CDX starting at p7 (4 g/kg body weight, dissolved in 0.9% NaCl) as recently described.⁹ All experiments were carried out in accordance to the German Protection of Animals Law. Hippocampal slices of mice (median days of...