Instituto Universitario de Biología Molecular

Molecular Bases of Neuronal Plasticity

Molecular neuropathology

Prof. Francisco Javier Díez-Guerra. Catedrático.  Departamento de Biología Molecular. UAM.

Higher cognitive functions differentiate humans from other animal species. These functions depend on the activity of complex neural networks in our forebrain. As we age or due to neurological or psychiatric disorders, these networks lose functionality caused by the dysfunction and loss of synapses and eventually neurodegenerative events. In the development of the mammalian central nervous system there are periods of active synaptogenesis and synaptic remodeling, driven by sensory experience and essential for the proper configuration of adult neural networks. Until we understand in depth how these high synaptic plasticity events work and how to induce them, it will be difficult to imagine actions to prevent, alleviate or recover the loss of cognitive functionality associated with age or pathologies. In our laboratory, we have been able to reproduce several features of these periods of high plasticity using in vitro models based on primary cultures of dissociated embryonic neurons. We have found that neuronal electrical activity is critical and want to understand the underlying molecular and cellular mechanisms. To this end, we are focused on determining how synaptic activity, and more specifically, local intracellular calcium (Ca+2) oscillations modulate signaling pathways leading to synapse production and reinvigoration. Calmodulin (CaM), a calcium-binding protein, transduces Ca+2 oscillations into intracellular signaling events that lead to short-term and long-term effects, including the modulation of gene expression patterns. CaM activity is locally regulated by proteins such as Neurogranin (Ng), an abundant CaM-sequestering protein in the post-synaptic compartment of forebrain neurons. Ng brain levels and cognitive performance are closely and directly correlated in the human brain. Therefore, we have set as our research goals the study of the regulation of Ng expression and its functional role in the postsynaptic environment. We use techniques in the areas of biochemistry, cellular and molecular biology, gene expression manipulation, transcriptomics, proteomics and advanced light microscopy and image analysis, and build genetically-encoded biosensors, to identify the actors and the interactions that are relevant for synaptic generation and remodeling. We propose Ng as a target for strategies to prevent, alleviate or cure impaired cognitive function. Since Ng expression is restricted to some forebrain areas and late developmental stages, interventions to promote Ng expression will be likely devoid of undesired side-effects. In summary, a deeper understanding of the role of CaM-sequestering proteins in synaptic plasticity will make it possible to develop new therapies to improve cognitive functions and quality of life of aging individuals and patients of neurological diseases.