THETA-NESTED GAMMA OSCILLATIONS-INDUCED LONG-TERM PLASTICITY DURING NEURONAL CIRCUIT DEVELOPMENT AND THE PROGRESSION OF ALZHEIMER’S DISEASE

Brain plasticity and oscillations interact in coding information and memory in the brain. Yet, the knowledge of the dynamics of neuronal activity that give rise to long-lasting experience traces responsible for memory during development is scarce. Moreover, plasticity and oscillations are impaired in Alzheimer’s disease, one of the most devastating neurodegenerative disorders without effective treatments. Combined studies and manipulation of plasticity and oscillations at early stages of the disease represent novel approaches aimed at early detection and therapeutic strategies. Here, we performed ex vivo electrophysiological recordings on hippocampal CA3-CA1 synapses in mouse brain slices. Likewise, we studied the mechanism and the developmental profile of theta-nested gamma oscillations-induced potentiation (TnG-LTP), and TnG-LTP impairment during AD progression in a novel AD mouse model. We observed that astrocytes are crucial for sensing the coincidence of activity, and the timing of this coincidence describes an asymmetric temporal window and sets the magnitude of the plasticity induced by interacting rhythmic activity in the brain. Moreover, TnG-LTP consistently emerges after the 3^rd postnatal week, involves postsynaptic NMDA-receptors and Ca²⁺. In addition, TnG-LTP is impaired in the 2-month-old APP-tau mouse, far before the onset of cognitive impairment and tau- and amyloid pathology and is completely absent at 6 months old. Thus, TnG-LTP might affect functions acquired later during development. Additionally, astrocytes may play a role in setting a threshold for the induction of plasticity during development, and this could represent a promising mechanism to target in Alzheimer´s disease models.