Spanish researchers have observed that synaptic activity enhances the expression of neurogranin, an abundant protein in the brain that participates in the processes of neuronal plasticity. The results, published in Molecular Neurobiology, also show that this protein promotes a higher density of synaptic contacts.
Neurogranin (Ng) is a brain protein related to the mechanisms of memory and learning. After analyzing cultures of hippocampal neurons, a team from the Autonomous University of Madrid (UAM) and the Severo Ochoa Molecular Biology Center (mixed center UAM-CSIC) has shown that the expression of neurogranin is regulated by synaptic activity, and that protein promotes a substantial increase in synaptic density in neural networks.
These results encourage the study of neurogranin as a molecular target for the development of strategies capable of preventing and alleviating cognitive deficits. These deficits coincide with the loss of cerebral synaptic contacts that are observed in aging and several neurodegenerative pathologies.
“We know that mice lacking neurogranin suffer from severe cognitive disability, although anatomically or physiologically they are apparently normal. In humans, low levels of this protein are associated with a high cognitive deterioration,” explains Raquel de Andrés, co-author of the paper.
“For example, patients with untreated congenital hypothyroidism have reductions of up to 60% in Ng content in several regions of the brain and a type of very pronounced mental retardation known as cretinism. Other conditions in which cognitive performance and neurogranin levels are related are aging and Alzheimer’s disease.”
In their study, the researchers were initially surprised to find that only 10% of the neurons in culture expressed adult levels of Ng, although in the hippocampus more than 90% of pyramidal neurons express high levels of Ng.
Francisco Javier Díez Guerra, the principal investigator of the group, said: “We discovered that a part of the expression of Ng is regulated by synaptic activity and is dependent on the activation of a synaptic receptor, the NMDA receptor, which transduces to the inside the neuron signals of the glutamate neurotransmitter.”
“We observe that the stimulations that induce synaptic potentiation produce a rapid fall of Ng levels, followed by a progressive recovery by local synthesis from mRNA located in dendrites. Using modified lentiviruses we obtain cultures in which more than 60% of the neurons express adult levels of Ng and we found that the synaptic density of these cultures is almost double that of control cultures, in which only 10% of the neurons express Ng.”
Synaptic plasticity and cognitive deterioration
Neurons are interconnected in the brain forming complex functional networks that store information. Our memories and knowledge are recorded in these networks in the form of ‘engrams’, that is, sets of connections between groups of neurons that were formed and stabilized at the moment of experience or learning.
The more synaptic density a neural network has, the greater the connectivity of the neurons that integrate it, and the greater its capacity to store and process information. Thus, memory is based on the modifications that occur in the synaptic circuits of our neural networks while we experience and learn.
During childhood and early adolescence, our brain experiences the greatest synaptic remodeling of all life. In this period, exposure and interaction with the physical, social and cultural environment that surrounds us shapes our neural networks and determines the motor, perceptual and cognitive skills that will shape our adult personality.
In recent decades, research in cellular and molecular neurobiology has revealed the central role of synaptic contacts in the processes of memory and learning.
One of the most important milestones has been the discovery of the basic molecular mechanisms of synaptic plasticity, the property that allows neurons to adapt their communication efficiency based on the activity they have previously experienced.
“Analogous to what happens with respiratory and muscular capacity when we perform physical exercise, the more synaptic circuits are exercised, the more they acquire storage and processing capacity,” the authors explain.
Recent studies have shown that cognitive deterioration associated with age or neurodegenerative diseases is related to a lower synaptic density of neural networks in areas of the forebrain. In these cases, before the first symptoms of cognitive deterioration are manifested, a significant reduction in synaptic density is already observed in areas such as the cerebral cortex or the hippocampus.
“This asymptomatic synaptic degeneration can last for years or decades,” the authors add. “When the synaptic loss is already substantial and the mechanisms of plasticity are not sufficient to maintain function, the first symptoms of cognitive deterioration appear. By then, synaptic degeneration is high and difficult to recover. ”