LAYER- AND REGION-SPECIFIC IMBALANCES IN CORTICAL INTERNEURONS IN THE DP(16)1YEY MOUSE MODEL OF DOWN SYNDROME

Down Syndrome (DS), caused by triplication of the human chromosome 21, is the most common neurodevelopmental disorder worldwide, associated with altered brain structure and function, physical abnormalities, and intellectual disability. Imbalance of cortical excitatory/inhibitory (E/I) circuitry was described in DS patients’ brains, but how specific cortical inhibitory circuit mediate DS pathophysiology remains unclear. Thus, we aimed at characterizing the DS mouse model Dp(16)1Yey, throughout development, and comprehend how cortical interneurons are affected in DS. Behavioral tests in male and female animals, showed that, starting at 1 month of age, Dp(16)1Yey mice showed anxiety- and obsessive compulsive-like behaviors and impaired long-term, spatial and social memories. This was accompanied by coordination and balance difficulties and hindlimb hypotonia, that worsened with age. Next, using immunostainings and alignment of slices with the Allen Brain Atlas, several subtypes of cortical interneurons were characterized in the prefrontal cortex (PFC) of 5-months-old mice. Reduced number of neurons was found in some layers of the anterior cingulate and prelimbic areas of the PFC along with an increased number of total GABAergic interneurons in Dp(16)1Yey mice. Also, the number of different interneuron subtypes (parvalbumin-, somatostatin-, and calbindin-positive neurons) was altered in this DS model, in a layer- and region-specific manner, pointing towards an imbalance in the E/I circuitry. The same analysis is currently being done in fetal and adult human brain tissue. Overall, these results highlight that the Dp(16)1Yey model mimics the clinical manifestations described in humans, while pointing to interneuron subtype imbalances as an important component of DS.