Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) are novel and powerful tools to investigate discrete neuronal populations in the brain. We have used DREADDs to stimulate degenerating neurons in a Down syndrome (DS) model, Ts65Dn mice. Individuals with DS develop Alzheimer's disease (AD) neuropathology and have elevated risk for dementia starting in their 30s and 40s. Individuals with DS often exhibit working memory deficits coupled with degeneration of the locus coeruleus (LC) norepinephrine (NE) neurons. It is thought that LC degeneration precedes other AD-related neuronal loss, and LC noradrenergic integrity is important for executive function, working memory, and attention. Previous studies have shown that LC-enhancing drugs can slow the progression of AD pathology, including amyloid aggregation, oxidative stress, and inflammation. We have shown that LC degeneration in Ts65Dn mice leads to exaggerated memory loss and neuronal degeneration. We used a DREADD, hM3Dq, administered via adeno-associated virus into the LC under a synthetic promoter, PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand clozapine-N-oxide. DREADD stimulation of LC-NE enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in controls. To confirm that the noradrenergic transmitter system was responsible for the enhanced memory function, the NE prodrug L-threo-dihydroxyphenylserine was administered in Ts65Dn and normosomic littermate control mice, and produced similar behavioral results. Thus, NE stimulation may prevent memory loss in Ts65Dn mice, and may hold promise for treatment in individuals with DS and dementia.

Cognitive Impairment, Neuroimaging, and Alzheimer Neuropathology in Mouse Models of Down Syndrome

“…DREADD stimulation of LC-NE neurons enhanced performance in a novel object recognition task and reduced hyperactivity in Ts65Dn mice, without significant behavioral effects in normosomic age-matched controls. We further confirmed that the NE transmitter system was responsible for the enhanced memory function, by administering the NE pro-drug L-threo-dihydroxyphenylserine (L-DOPS) in separate groups of Ts65Dn and NS mice, which produced similar behavioral results [137]. …”

“…2C, 3E and F), see also [128]. In further studies aimed at rescuing LC function, Fortress and Hamlett, et al used a Gq-coupled designer receptor exclusively activated by a designer drug (DREADD-hM3Dq) to selectively stimulate aged LC-NE neurons in Ts65Dn mice [137]. The DREADD receptor was administered via AAV into the LC under a synthetic promoter to dopamine-beta-hydroxylase (DBH), PRSx8, to selectively stimulate LC neurons by exogenous administration of the inert DREADD ligand, clozapine-N-oxide (CNO).…”

A Feasibility Study to Investigate Chemogenetic Modulation of the Locus Coeruleus by Means of Single Unit Activity

“…From our results and sequence of experimental steps, we conclude that the use of AAV2/7 is less desirable to specifically induce DREADD expression in LC neurons in comparison to previously used approaches. A different AAV serotype such as the AAV2/9 as discussed above leads to higher transduction levels (Vazey and Aston-Jones, 2014;Fortress et al, 2015;Kane et al, 2017;Rorabaugh et al, 2017;Cope et al, 2019;Zerbi et al, 2019). Other groups have even used a different type of viral vector (i.e., CAV) to induce the expression of opsins or engineered ligand gated ion channels in the noradrenergic neurons resulting in high expression patterns after direct injection in LC or administration in LC projection areas (Li et al, 2016;Hirschberg et al, 2017).…”

“…Alternatively site-specific recombinase technology can be used which consists of injecting a Cre-dependent AAV vector in TH-Cre transgenic mice. Previous research groups using AAVs mostly used an AAV2/9 which resulted in successful transduction of LC (Vazey and Aston-Jones, 2014;Fortress et al, 2015;Kane et al, 2017;Rorabaugh et al, 2017;Cope et al, 2019;Zerbi et al, 2019).…”

Mouse-based genetic modeling and analysis of Down syndrome

“…99 Specifically, in Ts65Dn mice, locus coeruleus showed progressive age-related changes in volume and cell number at 3-6 months of age, with changes in basal forebrain cholinergic neurons at 9-12 months. 44,[100][101][102][103] Another important AD neuropathology is enlargement of early endosomes. The implication is associated with the fact that APP processing occurs in endosomes.…”