Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome

Eric D. Hamlett, Aurélie Ledreux, Anah Gilmore, Elena M. Vazey, Gary Aston-Jones, Heather A. Boger, Daniel Paredes, Ann Charlotte E. Granholm

Research output: Contribution to journalArticle

Abstract

The pontine nucleus locus coeruleus (LC) is the primary source of noradrenergic (NE) projections to the brain and is important for working memory, attention, and cognitive flexibility. Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) with high penetrance and often exhibit working memory deficits coupled with degeneration of LC-NE neurons early in the progression of AD pathology. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools that allow targeted manipulation of discrete neuronal populations in the brain without the confounds of off-target effects. We utilized male Ts65Dn mice (a mouse model for DS), and male normosomic (NS) controls to examine the effects of inhibitory DREADDs delivered via an AAV vector under translational control of the synthetic PRSx8, dopamine β hydroxylase (DβH) promoter. This chemogenetic tool allowed LC inhibition upon administration of the inert DREADD ligand, clozapine-N-oxide (CNO). DREADD-mediated LC inhibition impaired performance in a novel object recognition task and reversal learning in a spatial task. DREADD-mediated LC inhibition gave rise to an elevation of α-adrenoreceptors both in NS and in Ts65Dn mice. Further, microglial markers showed that the inhibitory DREADD stimulation led to increased microglial activation in the hippocampus in Ts65Dn but not in NS mice. These findings strongly suggest that LC signaling is important for intact memory and learning in Ts65Dn mice and disruption of these neurons leads to increased inflammation and dysregulation of adrenergic receptors.

Original languageEnglish (US)
Article number104616
JournalNeurobiology of Disease
Volume134
DOIs
StatePublished - Feb 2020

Fingerprint

Designer Drugs
Locus Coeruleus
Memory Disorders
Down Syndrome
Short-Term Memory
Alzheimer Disease
Reversal Learning
Adrenergic Neurons
Penetrance
Brain
Mixed Function Oxygenases
Adrenergic Receptors
Hippocampus
Dopamine
Learning
Pathology
Ligands
Inflammation
Neurons
Population

All Science Journal Classification (ASJC) codes

  • Neurology

Keywords

  • Alzheimer's disease
  • Designer receptors exclusively activated by designer drugs (DREADD)
  • Down syndrome
  • Locus Coeruleus
  • Memory
  • Neuroinflammation
  • Norepinephrine

Cite this

Hamlett, E. D., Ledreux, A., Gilmore, A., Vazey, E. M., Aston-Jones, G., Boger, H. A., ... Granholm, A. C. E. (2020). Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome. Neurobiology of Disease, 134, [104616]. https://doi.org/10.1016/j.nbd.2019.104616
Hamlett, Eric D. ; Ledreux, Aurélie ; Gilmore, Anah ; Vazey, Elena M. ; Aston-Jones, Gary ; Boger, Heather A. ; Paredes, Daniel ; Granholm, Ann Charlotte E. / Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome. In: Neurobiology of Disease. 2020 ; Vol. 134.
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abstract = "The pontine nucleus locus coeruleus (LC) is the primary source of noradrenergic (NE) projections to the brain and is important for working memory, attention, and cognitive flexibility. Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) with high penetrance and often exhibit working memory deficits coupled with degeneration of LC-NE neurons early in the progression of AD pathology. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools that allow targeted manipulation of discrete neuronal populations in the brain without the confounds of off-target effects. We utilized male Ts65Dn mice (a mouse model for DS), and male normosomic (NS) controls to examine the effects of inhibitory DREADDs delivered via an AAV vector under translational control of the synthetic PRSx8, dopamine β hydroxylase (DβH) promoter. This chemogenetic tool allowed LC inhibition upon administration of the inert DREADD ligand, clozapine-N-oxide (CNO). DREADD-mediated LC inhibition impaired performance in a novel object recognition task and reversal learning in a spatial task. DREADD-mediated LC inhibition gave rise to an elevation of α-adrenoreceptors both in NS and in Ts65Dn mice. Further, microglial markers showed that the inhibitory DREADD stimulation led to increased microglial activation in the hippocampus in Ts65Dn but not in NS mice. These findings strongly suggest that LC signaling is important for intact memory and learning in Ts65Dn mice and disruption of these neurons leads to increased inflammation and dysregulation of adrenergic receptors.",
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Hamlett, ED, Ledreux, A, Gilmore, A, Vazey, EM, Aston-Jones, G, Boger, HA, Paredes, D & Granholm, ACE 2020, 'Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome', Neurobiology of Disease, vol. 134, 104616. https://doi.org/10.1016/j.nbd.2019.104616

Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome. / Hamlett, Eric D.; Ledreux, Aurélie; Gilmore, Anah; Vazey, Elena M.; Aston-Jones, Gary; Boger, Heather A.; Paredes, Daniel; Granholm, Ann Charlotte E.

In: Neurobiology of Disease, Vol. 134, 104616, 02.2020.

Research output: Contribution to journalArticle

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AU - Hamlett, Eric D.

AU - Ledreux, Aurélie

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AU - Aston-Jones, Gary

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AU - Paredes, Daniel

AU - Granholm, Ann Charlotte E.

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