Fernandez, F., & Reeves, R. H. (2015). Assessing cognitive improvement in people with Down syndrome: important considerations for drug-efficacy trials. Handbook of experimental pharmacology, 228, 335-80.
Experimental research over just the past decade has raised the possibility that learning deficits connected to Down syndrome (DS) might be effectively managed by medication. In the current chapter, we touch on some of the work that paved the way for these advances and discuss the challenges associated with translating them. In particular, we highlight sources of phenotypic variability in the DS population that are likely to impact performance assessments. Throughout, suggestions are made on how to detect meaningful changes in cognitive-adaptive function in people with DS during drug treatment. The importance of within-subjects evaluation is emphasized.
Fernandez, F., & Garner, C. C. (2007). Object recognition memory is conserved in Ts1Cje, a mouse model of Down syndrome. Neuroscience letters, 421(2), 137-41.
Ts1Cje and Ts65Dn are genetic mouse models of Down syndrome (DS). Like individuals with DS, these mice exhibit various hallmarks of hippocampal pathology, and deficits in hippocampal-based, declarative learning and memory tasks. Both spatial navigation and novel object recognition, two prototypical domains of declarative memory function, have been strongly characterized in the Ts65Dn DS model. Indeed, Ts65Dn mice show navigation problems in the Morris water maze, impaired alternation in a T-maze, and deficient working and reference memory in the radial arm maze task. They, likewise, show an inability to detect object novelty over time. In contrast to the Ts65Dn model, hippocampal-dependent cognition has been less well characterized in Ts1Cje. Although Ts1Cje mice have been found to exhibit spatial difficulties in the Morris water maze and reduced spontaneous alternation, their ability to process object-based information has never been examined. Here, we report that Ts1Cje mice perform normally in short-term and long-term novel object recognition tasks. The ability of Ts1Cje mice to detect object novelty, unlike Ts65Dn, may point to differences in the extent of hippocampal pathology in the two DS mouse models.
Fernandez, F., & Garner, C. C. (2007). Over-inhibition: a model for developmental intellectual disability. Trends in neurosciences, 30(10), 497-503.
Developmental intellectual disability (DID) is a daunting societal problem. Although tremendous progress has been made in defining the genetic causes of DID, therapeutic strategies remain limited. In particular, there is a marked absence of a unified approach to treating cognitive impairments associated with DID. Here, we suggest that the brain in many DID-related disorders is subject to a basic imbalance in neuronal activity, with an increased contribution of inhibition to neural circuits. This over-inhibition, in turn, is predicted to lead to deficits in synaptic plasticity and learning and memory. We further discuss possibilities for pharmacological intervention in DID, focusing on the concept of drug-induced 'therapeutic neuroadaptation' as a means of stably enhancing constitutive circuit excitability and cognition over time.
Fernandez, F., & Edgin, J. O. (2016). Pharmacotherapy in Down's syndrome: which way forward?. The Lancet. Neurology, 15(8), 776-7.
Fernandez, F., & Edgin, J. O. (2013). Poor Sleep as a Precursor to Cognitive Decline in Down Syndrome : A Hypothesis. Journal of Alzheimer's disease & Parkinsonism, 3(2), 124.
We propose that sleep disruption is a lever arm that influences how cognition emerges in development and then declines in response to Alzheimer disease in people with Down syndrome. Addressing sleep disruptions might be an overlooked way to improve cognitive outcomes in this population. This article is a contribution to a Special Issue on Down Syndrome curated by the editors of the Journal of Alzheimer's Disease & Parkinsonism.
