News and Publications

Molecular Basis of Cognitive Function and Dysfunction

M. Mayford, E. Korzus, K. Limbaeck-Stokin, G.J. Reijmers, M. Yasuda, R. Yasuda, S. Miller, J. Coats, T. Rodewald, K. Kass

The ability to remember is perhaps the most significant and distinctive feature of our cognitive life. We are who we are in large part because of what we have learned and what we remember. Impairments in learning and memory are a component of disorders that affect human beings throughout life, from childhood forms of mental retardation to psychiatric disorders such as schizophrenia with onsets in late adolescence and early adulthood to diseases of aging such as Alzheimer's.

We use genetic manipulation in mice to investigate the molecular events involved in learning and memory. We chose this approach for the following reasons: (1) Although many of the cognitive disorders in humans have a major genetic component, in many instances, determining the causative genes has been difficult. (2) Of the genetically accessible experimental organisms, mice are the most similar to humans in both genetic makeup and brain structure, so insights gained in mice most likely will be applicable to humans. (3) Understanding the genes involved in a process can indicate molecular targets that might be amenable to therapeutic intervention.

CALCIUM SIGNALING AND MEMORY

We know relatively little at a molecular level about how the brain stores new information. One hypothesis, which we tried to test, is that calcium-regulated changes in the strength of synaptic connections between nerve cells can store information. We generated 2 different types of mutant mice that have altered calcium signaling molecules either at the synapse or in the cell nucleus. Calcium/calmodulin-dependent protein kinase is abundant at synapses and when activated by calcium can alter the strength of synaptic connections. We used genetic manipulations to indiscriminately activate this kinase at all synapses in certain parts of the brain and found that when the kinase is activated, not only is the formation of new memory impaired but also previously established memories are erased. If memories are stored as precise patterns of synaptic weights, then the indiscriminate altering of these synaptic weights might be expected to erase memories.

Formation of stable long-lasting memories requires not just the modification of preexisting proteins in the neuron but also the expression of new genes in the nucleus. We generated mutant mice in which the general calcium signaling molecule calmodulin was specifically inhibited in the nucleus to test the role that this signaling plays in long-term memory storage. We found that although these mice could learn and remember new information, the memory did not last more than a few hours. This finding suggests that calcium activation of new gene expression is required for the conversion of short-term to long-term memories. It will be interesting to determine which genes are induced by calcium and how the activation of these genes is altered in the mutant mice.

GENETIC SCREENS FOR LEARNING AND MEMORY MUTANTS

The recent determination of the complete sequences of the mouse and human genomes makes a classical approach to genetics practical in the mouse. Rather than asking whether mutation of a particular gene affects learning and memory, we can ask simply what genes when mutated affect learning and memory. We are using this classical genetic approach in collaboration with the Genomics Institute of the Novartis Research Foundation, San Diego, California. We have already identified 7 families of mice in which mutation of a single gene alters various aspects of learning and short- and long-term memory. Identification of the causative mutations in these families should provide useful insights into the molecular machinery that underlies this critical cognitive function.

PUBLICATIONS

Bejar, R., Yasuda, R., Krugers, H., Hood, K., Mayford, M. Transgenic calmodulin-dependent protein kinase II activation: dose-dependent effects on synaptic plasticity, learning, and memory in mice. J. Neurosci. 22:5719, 2001.

Glazewski, S., Bejar, R., Mayford, M., Fox, K. The effect of autonomous a-CaMKII expression on sensory responses and experience-dependent plasticity in mouse barrel cortex. Neuropharmacology 41:771, 2001.

Miller, S., Yasuda, M., Coats, J.K., Jones, Y., Martone, M.E., Mayford, M. Disruption of dendritic translation of CaMKIIa impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36:507, 2002.