Designer receptors enhance memory in a mouse model of Down syndrome

J Neurosci. 2015 Jan 28;35(4):1343-53. doi: 10.1523/JNEUROSCI.2658-14.2015.


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.

Keywords: Down syndrome; designer receptors; hippocampus; locus coeruleus; neurodegeneration; noradrenergic.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / therapeutic use*
  • Cell Count
  • Clozapine / analogs & derivatives*
  • Clozapine / therapeutic use
  • Cross-Over Studies
  • Designer Drugs
  • Disease Models, Animal
  • Down Syndrome / complications*
  • Down Syndrome / genetics
  • Exploratory Behavior / drug effects
  • Exploratory Behavior / radiation effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Humans
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / metabolism
  • Locus Coeruleus / pathology
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology*
  • Mice
  • Mice, Neurologic Mutants
  • Motor Activity / drug effects
  • Motor Activity / genetics
  • Neurodegenerative Diseases / etiology
  • Receptor, Muscarinic M3 / genetics
  • Receptor, Muscarinic M3 / metabolism*
  • Serine / therapeutic use


  • 3-(4-(methylthio)phenylserine)
  • Antipsychotic Agents
  • Designer Drugs
  • Receptor, Muscarinic M3
  • Serine
  • Clozapine
  • clozapine N-oxide