Neural correlates of memory impairment and rescue in a mouse model of down syndrome

Resumen

Understanding the neural correlates of intellectual disability is still a central and unresolved problem in neuroscience. In this thesis we have unraveled several candidate neural substrates of memory impairment and rescue using a well-established mouse model of Down syndrome (DS) and three validated pro-cognitive strategies. DS is the most common form of intellectual disability and results from one of the most complex genetic perturbations that is compatible with survival, trisomy 21. DS is accompanied by abnormal neuro-architecture, deficient synaptic plasticity, and excitation-inhibition imbalance in critical brain regions for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Here, we recorded neural activity simulta- neously from the PFC and HPC of trisomic Ts65Dn male and female mice and their non-trisomic littermates during quiet wakefulness, natural sleep and memory acquisition and retrieval via the novel object recognition task. Trisomic mice showed recognition memory deficits that were accompanied by hypersynchronised neural activity in the PFC and HPC and exaggerated PFC-HPC functional connectivity, particularly at theta ranges. We speculate that this pathological theta hypersynchronisation in TS mice is caused by an overinhibition as it was rescued by blocking the GABAergic system with α5IA, a GABAA receptor inverse agonist. We also assessed whether memory deficits could be caused by poor memory consolidation during sleep and found that Ts65Dn mice showed ripple alterations that predicted poor memory performance and were rescued by two non-pharmacological pro-cognitive treatments, epigallocatechin-3- galate (EGCG) and environmental enrichment (EE). Detailed analyses of neural activity while animals were performing the memory task revealed that memory acquisition depends on PFC-to- HPC theta connectivity whereas memory retrieval depends on HPC- to-PFC low gamma connectivity. Both memory biomarkers predicted successful memory performance in healthy mice, were disrupted in trisomic mice and rescued by EGCG and EE in male and female trisomic mice, respectively. This strongly suggests that PFC-HPC theta and gamma connectivity contribute to memory acquisition and retrieval. Collectively, we identified unique neurophysiological biomarkers that are candidate cellular mechanisms underlying intellectual disability and sleep disturbances in DS. This thesis also highlights potential neural substrates of cognitive rescue taking advantage of three promising therapeutic strategies in DS.