Communication between neurons is required for normal brain function. Synapses are specialized junctions through which neurons signal to one another to form interconnected neural circuits. They are thus crucial to the biological computations that underlie perception and thought. They also provide the means through which the nervous system connects to and controls the other systems of the body. Although synapses between neurons and muscles outside of the brain have been the focus of intensive research, the scientific community is only just beginning to decipher the mechanisms by which synapses are established within the brain. Even in these early stages of research, it is apparent that there are fundamental differences in the molecules that drive the establishment, consolidation and maintenance of neuron-neuron synapses. Indeed, it is clearly evident that we do not even know all the molecular players involved in the interaction.
Dr. Millen’s lab is addressing this question through analysis of a spontaneous mouse mutant called tippy, so named because these mice have a characteristic uncoordinated, or “tippy” behavior. They have determined that this uncoordinated behavior is a result of abnormally formed connections between Purkinje cells in the cerebellum and their partners, the climbing fibers of the inferior olivary nucleus in the brain stem. We have also discovered many other connection abnormalities in other parts of the brain in tippy mice which contribute to their other abnormal behaviors such as severe epilepsy. The gene(s) that is mutated in these mice must therefore normally act to regulate the normal establishment neuronal synapses. Tippy is a spontaneous mutant and therefore we do not know which gene abnormalities cause the neuronal defects. Using genetic analysis, we defined the location of the tippy gene, mapping it to a region of mouse chromosome 9 where none of genes present have previously been implicated in neural development or function. We have sequenced all of the protein encoding regions of these genes and not found the mutation. Thus, the mutation must lie in a surrounding sequences that regulate the expression of the genes in this region of chromosome 9. The most efficient way to identify the tippy mutation is to sequence all’ of these regulatory sequences – a large, yet feasible undertaking. Without the identification of the DNA sequence change of in tippy mutants, it is unlikely that NIH funds can be obtained to continue this important project. Funding from the BRF would facilitate the collection of this critical data.
Tippy mice model both cerebellar dysfunction and epilepsy – both significant, but poorly understood contributors to mortality and morbidity in children. We have determined that tippy mutant mice have abnormalities in the way neurons communicate with each other and disruption of this communication in a similar manner is likely to cause cerebellar dysfunction and epilepsy in humans. While clinically relevant, the findings from the study of these mice have a much broader implications. Extensive research in the last decade has demonstrated that many common neurological disorders (such as epilepsy and Alzheimer’s) and psychiatric disorders (including schizophrenia and autism) are fundamentally disorders of neuronal communication. Understanding the molecular machinery of how neurons regulate the establishment of synapses to communicate is certain to prove invaluable to the discovery of new drugs and treatment options for a multitude of debilitating neurological disorders.

Other Grants

Lindsay M. De Biase, Ph.D., University of California Los Angeles
The Role of Microglial Lysosomes in Selective Neuronal Vulnerability
Synapses, the sites of signaling between neurons in the brain, play essential roles in learning, memory, and the health of neurons themselves. An enduring mystery is why some neurons are…
How the Nervous System Constructs Internal Models of the External World
As animals navigate their environments, they construct internal models of the external sensory world and use these models to guide their behavior. This ability to incorporate ongoing sensory stimuli into…
Xiaojing Gao, Ph.D., Stanford University
When Neural Circuits Meet Molecular Circuits: Quantitative Genetic Manipulation with Single-cell Consistency
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that…
Rafiq Huda, Ph.D., Rutgers University
Conducting the Orchestra of Movement—Functional Role of Striatal Astrocytes in Health and Disease
Movement requires coordinated activity across a large brain-wide network. The striatum is a particularly important part of this circuit; it integrates motor-related information from many distinct brain regions to regulate…