News and Publications

Molecular Basis of Cognitive Function and Dysfunction

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 that 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.

Gene Expression At Synapses and Cognitive Disorders

Synapses are critical sites of communication between nerve cells, and changing the strength of synapses may be one mechanism by which memories are stored. Fragile X syndrome, a common form of mental retardation, is caused by mutations in a gene that regulates the translation of other genes at the synapse. One of those synaptically regulated genes codes for calcium/calmodulin-dependent protein kinase. We showed that mutations in the gene for this kinase that prevent normal translation of the enzyme at the synapse produce a syndrome characterized by a loss of plasticity at the synapse and a severe impairment in long-term memory. These findings suggest that the dysregulation of calcium/calmodulin-dependent protein kinase may contribute to the cognitive deficits associated with fragile X syndrome.

Calcium Signaling and Memory

If memories are stored by changes in synaptic strength, then the precise pattern of the synaptic weights carries the information. The indiscriminate altering of the relationships between synaptic weights might be expected to erase memories in the same way that writing all 1's or 0's on a computer hard drive destroys information. Expression of a mutant form of calcium/calmodulin-dependent protein kinase can be used to indiscriminately activate the kinase at all synapses in specific regions of the brain. When we indiscriminately activated the kinase in excitatory forebrain neurons of mice, synaptic transmission was potentiated and previously established memories were disrupted. These results suggest that this kinase is a central mediator of the molecular changes that store information in the brain and that the specific pattern of activation of the kinase during learning encodes the information.

Formation of stable long-lasting memories requires not just the modification of preexisting proteins at the synapse 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 calmodulin-induced gene expression plays in long-term memory. 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.

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, 2002.