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 language | English (US) |
|---|---|
| Article number | 104616 |
| Journal | Neurobiology of Disease |
| Volume | 134 |
| DOIs | |
| State | Published - Feb 2020 |
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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
}
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 journal › Article
TY - JOUR
T1 - Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome
AU - Hamlett, Eric D.
AU - Ledreux, Aurélie
AU - Gilmore, Anah
AU - Vazey, Elena M.
AU - Aston-Jones, Gary
AU - Boger, Heather A.
AU - Paredes, Daniel
AU - Granholm, Ann Charlotte E.
PY - 2020/2
Y1 - 2020/2
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Designer receptors exclusively activated by designer drugs (DREADD)
KW - Down syndrome
KW - Locus Coeruleus
KW - Memory
KW - Neuroinflammation
KW - Norepinephrine
UR - http://www.scopus.com/inward/record.url?scp=85074342889&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074342889&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2019.104616
DO - 10.1016/j.nbd.2019.104616
M3 - Article
C2 - 31678403
AN - SCOPUS:85074342889
VL - 134
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
M1 - 104616
ER -