Brain plasticity is the ability to change in response to experience. Particularly, synaptic plasticity might involve structural and functional modifications of the connections (synapses) established between the neurons. These synaptic modifications depend on activity, like environmental inputs and experience. Meanwhile, brain rhythms, another property of the brain, emerge from rhythmic electrical activity in brain circuits. Both synaptic plasticity and brain rhythms are related to memory, which is an essential brain property for our identity and our ability to socially interact. Correct brain development is crucial for its functioning and to warrant accurate information processing and memory.
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 is insufficient. Moreover, plasticity and oscillations are impaired in Alzheimer’s disease and other neurological disorders. Thus, studying both processes in healthy and pathological conditions is important for human health, for basic and translational biomedical research.
In the last 20 years, research on Alzheimer’s disease focusing on removing toxic protein accumulation in the patient’s brain has led to failures in clinical trials. A new promising horizon of therapeutic attempts has emerged. It includes early detection and the search for other therapeutic targets. Such novel strategies may include integrative approaches. For example, a combined study and manipulation of plasticity and oscillations at early stages of the disease (yet in Alzheimer’s models) represents novel approaches, as we have conducted in this project, and we will follow up based on project results.
The main significance of the project is based on the current scenario for Alzheimer’s disease, which is a neurodegenerative disease clinically characterized by progressive memory loss affecting more than 55 million people worldwide (over 60% living in low- and middle-income countries). Today, no effective treatments exist. This reveals an increasing social and economic burden on society. As the proportion of older people in the population is increasing in nearly every country, this number is expected to rise to 78 million in 2030 and 139 million in 2050, meaning that we will face a looming epidemic of Alzheimer’s. Healthcare systems will be challenged to meet the needs of patients and their caregivers. The worldwide costs will be huge, and the prevention and early detection of AD is a global ambition.
Finally, the overall objectives followed in this project are to uncover key mechanisms underlying synaptic plasticity and brain rhythms during typical brain development and compare them to the progressive impairment of known cognitive-relevant neuronal circuit functions in models of Alzheimer´s disease. It will reveal basic mechanisms for manipulation in the disease models, a strategy that can bring us putative therapeutic targets more effective than the existing ones. These approaches can foster research and preclinical studies in many laboratories and companies worldwide working on Alzheimer´s disease therapeutic research and early interventions on the disease. During the project implementation, we established a two-way transfer of knowledge for achieving not only scientific results but also acquiring skills that will help us drive forward research to accelerate the finding of effective treatment for Alzheimer’s and for strengthening the career prospects of the researcher promoting his inclusion as consolidated researcher in the Spanish System of Science within this research field.
Figure caption. Theta-nested gamma oscillations-induced Long-Term Potentiation (TnG-LTP) in the mouse hippocampus, emerging in adulthood and lost in Alzheimer’s disease. A) Schematic representation of a brain slice showing the hippocampus and the placement of the stimulating (Stim.) and recording (Rec.) electrodes in the Schaffer collaterals (SC) and CA1 area. B) Real electrophysiological recording and stimulation protocol for the induction of TnG-LTP showing the recording of action potential firing from the pyramidal cell neuron (top), the stimulation of the neuron delivered via patch pipette (middle), 10 milliseconds after the stimulation of the SC (bottom). C) Schematic representation showing that the magnitude of the plasticity studied (TnG-LTP) increases during typical brain development (blue) in healthy conditions, emerging at adulthood. We observed that this plasticity is present in an adult mouse model of Alzheimer’s disease (orange), while this kind of synaptic plasticity is lost when the disease progresses and is clinically established at 6 months of age.
