Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

Designer Receptors Enhance Memory in a Mouse Model of Down Syndrome

“…Previously, our laboratory has shown that the loss of LC-NE can exacerbate cognitive impairment and neuropathology in Ts65Dn mice (Lockrow et al, 2011), suggesting a role for NE dysfunction in the accelerated neuropathology observed in Ts65Dn mice. We observed that artificially restoring LC-NE function via selective hM3Dq/CNO-mediated LC activation and via the NE prodrug L-DOPS enhanced hippocampal-dependent memory in Ts65Dn mice, both of which corroborate the findings of others demonstrating a role for NE in facilitating cognition (Salehi et al, 2006(Salehi et al, , 2009Dang et al, 2014). Our group has recently shown that stimulation of hM3Dq DREADD receptors in the LC-NE neurons by systemic injection of the inert DREADD ligand CNO doubles the firing frequency of LC-NE neurons and facilitates cortical EEG changes (Vazey and Aston-Jones, 2014), suggesting that activation of hM3Dq receptors following CNO administration can drive LC neuronal firing rates.…”

“…The DREADD/CNO experiment further demonstrates that acute activation of a residual, albeit degenerating, LC-NE pathway, is sufficient to normalize deficits in hippocampal-dependent memory in Ts65Dn mice. This is supported by evidence that pharmacologically restoring NE levels in Ts65Dn mice and in Dbh-deficient mice enhances hippocampal-dependent memory (Salehi et al, 2009;Dang et al, 2014;Murchison et al, 2011). In addition to enhanced performance in the NORT, the LC-NE stimulation in Ts65Dn mice via CNO gave rise to increased time spent in the center and reduced hyperactivity in the spontaneous locomotion chamber.…”

“…Mice deficient in dopamine-␤-hydroxylase (D␤H knock-out mice) exhibit memory retention deficits that can be reversed by treatment with the ␤1 agonist xamoterol (Murchison et al, 2004). In humans with DS, the LC undergoes an accelerated and significant degeneration by as much as 60% compared with agematched non-DS brains (German et al, 1992). The LC-hippocampal NE circuit is important for blood-brain barrier integrity, regulating neuroinflammatory processes, and has direct effects on learning and memory (for review, see O'Donnell et al, 2012).…”

“…The LC-neurons degenerates early in AD and in DS-AD (Mann et al, 1986;German et al, 1992). LC-NE lesions, using the selective NE neurotoxin DSP-4 [N-(2-chloroethyl)-Nethyl-2-bromobenzylamine], leads to aggravated amyloid pathology in AD mouse models (Kalinin et al, 2007), and we have demonstrated that AD neuropathology and cognitive impairment are aggravated by LC-NE lesions in a mouse model of DS, the Ts65Dn mouse (Lockrow et al, 2011).…”

Assessing Cognitive Improvement in People with Down Syndrome: Important Considerations for Drug-Efficacy Trials

“…The corpus of work in Ts65Dn has suggested that selective overexpression of Hsa21 orthologs under physiological control can phenocopy significant aspects of DS in animals and that the mice themselves might be platforms for the discovery of drugs that mitigate intellectual disability in children and adults born with trisomy (Fernandez and Garner 2008;Hyde et al 2001;Smith et al 2014). Since the mid 2000s, several different drug classes have shown an ability to improve rudimentary behavioral indices of declarative learning and memory in the Ts65Dn model, including GABA antagonists (Fernandez et al 2007) and inverse agonists (Braudeau et al 2011a, b), open-channel antagonists of the NMDA receptor (Costa et al 2008), Smoothened agonists (SAG; Das et al 2013), compounds that stimulate norepinephrine (Dang et al 2014;Salehi et al 2009), and dietary choline (Moon et al 2010). It remains to be seen whether any of these agents will prove to be similarly efficacious in people, though some early signs are encouraging.…”