A new approach to understanding cognitive disabilities in Down syndrome

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Project Summary Down syndrome (DS), caused by a third copy of the human chromosome 21 (Hsa21), occurs in about 1 of every 700 births in the U.S. DS is the leading cause of genetically-defined intellectual disability, with a serious impact on public health. Several neurodevelopmental hypotheses for cognitive disabilities in DS have been proposed, but one of the most compelling is the GABAergic hypothesis for DS, which postulates that alterations in GABA signaling in early brain development may contribute to its neuropathology. Recent studies have found that a mouse model of DS, Dp(16)1Yey/+ mice (hereafter called Dp16), shows a similar deficit seen in patients with DS, including reduced cortical GABAergic interneurons. Despite the importance of prefrontal cortex (PFC) in higher cognitive processes and the observed functional impairments in PFC of people with DS, little is known about the neurobiological mechanisms that mediate the detrimental effects of altered GABAergic neuronal activity on PFC development and cognition in DS. In order to understand how these impairments arise, it is necessary to first understand the basic cellular and synaptic mechanisms of GABAergic regulation of brain function and how they are altered in the DS brain. In this R21 proposal, we utilize a novel combination of tools including two-photon microscopy, electrophysiology, chemogenetics, and in vivo pharmacological manipulation to test our central hypothesis that decreased inhibitory neuronal activity weakens GABAergic synapses and induces abnormal excitatory synapse maturation via heterosynaptic crosstalk in the PFC of Dp16. Guided by our strong preliminary data, we will examine this hypothesis in two specific aims: 1) Determine whether Dp16 mice exhibit structural and functional alterations of inhibitory and excitatory synapses on layer 2/3 pyramidal neurons in the PFC. 2) Determine the role of inhibitory activity in excitatory synapse maturation in the PFC of Dp16. Results from this exploratory study will further our understanding of the unique and detailed mechanisms by which GABA regulates brain development, with critical relevance to cellular underpinnings of PFC dysfunction and intellectual disability in DS. We expect that our results will highlight new avenues into the investigation of the pathophysiology underlying DS resulting from early perturbation of GABA signaling.