DOI: 10.5061/dryad.4j0zpc8mw
title: A therapeutic small molecule enhances γ-oscillations and improves cognition/memory in Alzheimer’s disease model mice

description: Brain rhythms provide the timing for the recruitment of brain activity
 required for linking together neuronal ensembles engaged in specific
 tasks.  The γ-oscillations (30-120 Hz) orchestrate neuronal
 circuits underlying cognitive processes and working memory. These
 oscillations are reduced in numerous neurological and psychiatric
 disorders, including early cognitive decline in Alzheimer’s disease (AD).
 Here we report on a potent brain-permeable small molecule, DDL-920 that
 increases γ-oscillations and improves cognition/memory in a mouse model of
 AD, thus showing promise as a new class of therapeutics for AD. We
 employed anatomical, in vitro, and in vivo electrophysiological, and
 behavioral methods to examine the effects of our lead therapeutic
 candidate small molecule. As a first in CNS pharmacotherapy, our lead
 molecule acts as a potent, efficacious, and selective negative allosteric
 modulator (NAM) of the γ-aminobutyric acid type A receptors (GABAARs) most
 likely assembled from α1β2δ subunits. These receptors, identified through
 anatomical and pharmacological means, underlie the tonic inhibition of
 parvalbumin (PV) expressing interneurons (PV+INs) critically involved in
 the generation of γ-oscillations. When orally administered twice daily for
 two weeks, DDL-920 restored the cognitive/memory impairments of
 3-4-month-old AD model mice as measured by their performance in the Barnes
 maze.  Our approach is unique as it is meant to enhance cognitive
 performance and working memory in a state-dependent manner by engaging and
 amplifying the brain’s endogenous γ-oscillations through enhancing the
 function of PV+INs.
description: # A therapeutic small molecule enhances γ-oscillations and improves
 cognition/memory in Alzheimer’s disease model mice
 [https://doi.org/10.5061/dryad.4j0zpc8mw](https://doi.org/10.5061/dryad.4j0zpc8mw) ## Description of the data and file structure This dataset contains individual data points represented in respective figures. The files with the extension .xlsx are Excel files and represent the data displayed in the graphs from the respective figures indicated in the file names. Fig2A_B.xlsx has two Sheets. Sheet "Fig2A" contains the data displayed in Fig2A representing the tonic GABA current after subtraction of gabazine (-GBZ) normalized by the whole-cell capacitance (cap). The units are A/F. Column A contains the data during the control period, and column B the data during the perfusion of tracazoate (10 uM). The number of cells is 5. Sheet "Fig2B" contains the data displayed in Fig2B representing the tonic GABA current after subtraction of gabazine (-GBZ) normalized by the whole-cell capacitance (cap). The units are A/F. Column A contains the data during the control period, and column B the data during the perfusion of DDL-920 (1 nM). The number of cells is 5. Fig2E_F.xlsx has two Sheets. Sheet "Fig2E" contains the data displayed in Fig2E representing the time-dependent changes in the power (RMS) of gamma oscillations recorded in vitro during perfusion of two concentrations of DDL-920. Column A represents time (in minutes). Columns B and C represent the mean RMS (Mean) and its standard deviation (SD) during the perfusion of the slices with vehicle (n=24). Columns D and E represent the mean RMS (Mean) and its standard deviation (SD) during the perfusion of the slices with 1 nM DDL-920 (n=22). Columns F and G represent the mean RMS (Mean) and its standard deviation (SD) during the perfusion of the slices with 100 nM DDL-920 (n=16). The vehicle and drug perfusions took place between 10-30 minutes on the time scale. Sheet "Fig2F" contains the data displayed in Fig2F representing the time-dependent changes in the power (RMS) of gamma oscillations recorded in vitro during perfusion of a single concentration (100 nM) of DDL-920 in slices from wild type (WT) and Alzheimer's disease model mice (AD). Column A represents time (in minutes). Columns B and C represent the mean RMS (Mean) and its standard deviation (SD) during the perfusion of the WT slices with 100 nM DDL-920 (n=6 slices, 3 mice). Columns D and E represent the mean RMS (Mean) and its standard deviation (SD) during the perfusion of the AD slices with 100 nM DDL-920 (n=6 slices, 3 mice). The drug was perfused between 10-15 min. Fig3H.xlxs has four sheets and contains the data displayed in Fig3H for the in vivo recordings of brain oscillations. Sheet "MI" is the modulation index (MI) as defined in the Methods for the modulation of the gamma oscillation amplitudes by the phase of theta oscillations. Column A (Pre) is the value of MI before the administration of 10 mg/kg DDL-920 in vivo, while in column B (Post) the value of the MI is shown for the period after the drug administration. The values in each row are obtained from the same animal (n=5). Sheet "gamma-RMS" is the gamma oscillation power (RMS) as defined in the Methods representing the power of the gamma oscillation recorded in vivo. Column A (Pre) is the value of gamma-RMS before the administration of 10 mg/kg DDL-920 in vivo, while in column B (Post) the value of the gamma-RMS is shown for the period after the drug administration. The values in each row are obtained from the same animal (n=5). Sheet "g-frequency" is the mean gamma oscillation frequency (Hz) as representing the mean frequency of the gamma oscillations recorded in vivo. Column A (Pre) is the value of gamma-frequency before the administration of 10 mg/kg DDL-920 in vivo, while in column B (Post) the value of the gamma-frequency is shown for the period after the drug administration. The values in each row are obtained from the same animal (n=5). Sheet "T-frequency" is the mean theta oscillation frequency (Hz) as representing the mean frequency of the theta oscillations recorded in vivo. Column A (Pre) is the value of theta-frequency before the administration of 10 mg/kg DDL-920 in vivo, while in column B (Post) the value of the theta-frequency is shown for the period after the drug administration. The values in each row are obtained from the same animal (n=5). Fig4D_F.xlsx has three Sheets. Sheet "Fig4D" contains the data displayed in Fig4D representing data obtained from the Barnes maze behavior of the three experimental groups of mice: Alzheimer's disease model mice treated with vehicle (AD+VEH), Alzheimer's disease model mice treated orally with 10 mg/kg DDL-920 (AD+DDL-920), and wild-type mice treated with vehicle (WT+VEH). In each treatment group, there are four columns: "Target", "Left", "Right", and "Opposite". These represent the four quadrants indicating their relationship to the quadrant in which the escape hole was located ("Target"). The values in each column are the fraction of total time spent in the respective quadrant. Each row represents the values obtained for an individual mouse, while the last line indicates the mean values for the fractions spent in the respective quadrants. Sheet "Fig4E" contains the data displayed in Fig4E representing the latencies (in s) until the animals reached the target hole obtained from the Barnes maze behavior of the three experimental groups of mice: Alzheimer's disease model mice treated with vehicle (AD+VEH), Alzheimer's disease model mice treated orally with 10 mg/kg DDL-920 (AD+DDL-920), and wild-type mice treated with vehicle (WT+VEH). Sheet "Fig4F" contains the data displayed on Fig4F representing the path lengths (in m) covered by the animals until reaching the target hole obtained from the Barnes maze behavior of the three experimental groups of mice: Alzheimer's disease model mice treated with vehicle (AD+VEH), Alzheimer's disease model mice treated orally with 10 mg/kg DDL-920 (AD+DDL-920), and wild-type mice treated with vehicle (WT+VEH). Files with extension .pxp are Igor files (created with IgorPro8, Wavemetrics - a free version of the program for examining the files can be downloaded from (https://www.wavemetrics.com/software/igor-pro-8). These files contain the data for the figures shown in the file names and also contain the respective statistical analyses performed in Igor Pro8. ## Sharing/Access information NA ## Code/Software NA