Neuroscience
In previous reports, CSHL neurobiologist Hollis Cline described the role of the enzyme CaMKII in neuronal development. In 1997, her lab built on its previous discoveries-that expression of CaMKII is involved with neuronal maturation and with the stabilization of synapses, the intricate connections between neurons. Evidence from the Cline lab showed that CaMKII coordinates the development of the physical structure of neurons with the development of their synaptic connections. The normal, gradual increase of CaMKII expression during early brain development correlates with slowed growth rate and increased stabilization of dendrites-the branches through which neurons receive their electrochemical signals. These changes signify neuronal maturity. Holly therefore hypothesized that CaMKII, which is regulated by calcium activity, may represent an activity-dependent mediator of neuronal maturation. Her lab tested this theory by forcing the expression of CaMKII in immature neurons and obtained the exciting result that indeed CaMKII expression suppressed the development of additional, longer dendrites and prompted the stabilization of the existing branches. Thus, it promoted the maturation of neurons during brain development.
Conversely, Holly and research investigator Elly Nedivi showed that a novel protein, CPG15, increases the number of dendritic branches in neurons. Elly isolated the gene for CPG15, which belongs to a group of genes whose expression is elevated by neuronal activity. In addition to inducing neuronal branching, they found that CPG15 also controls the growth of neighboring neurons through an intercellular signaling mechanism. These studies suggest that CPG15 is capable of translating local neuronal activity into structural changes in the brain. This would represent the discovery of a new class of neuronal activity regulated growth factors.
Alcino Silva's lab continues to study the molecular and behavioral functions involved in learning and memory in mice. In 1997, Alcino tied previous results together through an experiment with collaborator Howard Eichenbaum of Boston University in which he monitored the activity of specific cells in the hippocampus in the brains of living, functioning mice.
Alcino has been studying "place cells"-specific, identifiable brain cells that fire only when an animal is in a precise place in its environment, a place that the animal's brain recognizes. These place cells are representative of the "place circuits" that are stimulated as an animal becomes acquainted with a place or area. The establishment of such a series of circuits is called spatial orientation or learning; the mouse recognizes familiar things as it travels about. Alcino tested the function of place cells in two types of mutant mice, each representing a component in learning and memory that Alcino has been studying-the aCaMKII protein and a CREB protein. Alcino created genetically modified mice that carry a point mutation in a single amino acid of the aCaMKII protein. Instead of firing at specific times like wild-type cells, place cells in animals with this aCaMKII mutation fire randomly when they are exposed to familiar and unfamiliar places, which indicates a lack of learning. Mice containing decreased levels of CREB also display this reduced learning, albeit to a lesser degree. Behavioral studies corroborate this finding, as the same mutant mice demonstrate a marked lack of spatial orientation.
In a second set of experiments, Alcino's lab successfully reversed the learning deficit in mice with the NF1 mutation characteristic of neurofibromatosis type 1. These mice have proven to be a valuable model for the study of this disease. He has confirmed a mechanism that is defective in NF1 mice and has restored the ability of mice to learn by breeding in a second mutation that counteracts the effects of the NF1 mutation. These behavioral studies may suggest targets for the search for treatments of learning deficiencies in children affected by mutations in the neurofibromatosis type 1 gene.