Periodic Reporting for period 1 - STDP-development-AD (Neuronal networks dynamics underlying spike timing precision during brain developmental plasticity and Alzheimer's disease progression.)
Reporting period: 2023-01-01 to 2025-04-30
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.
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.
For achieving the ambitious project objectives, we used sophisticated multidisciplinary techniques. One of the main techniques used was the electrophysiological recording of neuronal activity combined with pharmacological manipulations and imaging. We found that there is a form of synaptic plasticity that can be induced in a region of the brain closely related to memory and learning processes: the hippocampus. This form of plasticity is induced by coincident electrical stimulation between two regions of this structure (CA3 and CA1). We paired the stimulus between CA3 and CA1 in two frequencies that mimic brain rhythm interactions. These rhythms are named theta and gamma oscillations, and they are closely related to brain states and memory formation. We also found that this form of plasticity induced by mimicking rhythmic interaction is impaired in a novel model of Alzheimer’s disease and that this mechanism involves an important type of brain cell population: the astrocytes.
Our results indicate that astrocytes are crucial for sensing the coincidence of activity, and the coincidence of activity sets the magnitude of the plasticity induced by interacting rhythmic activity in the brain. Moreover, this interaction only induces plasticity (in this case, it is potentiation of synaptic transmission) in this neuronal circuit during brain development in adulthood. In the early stages, it fails to produce an enhancement of the efficacy of communication between these two regions of the hippocampus. It might have an impact on functions that are acquired later during development, but it convincingly represents a door already opened for further investigation. Also, the astrocytes might have an implication in setting this threshold for induction of plasticity during development, and it might represent a promising mechanism to target in the Alzheimer´s disease model, another newly opened door for future research.