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

Sarah C. Goetz, Ph.D., Duke University
Uncovering a Novel Role for Primary Cilia in Eph/Ephrin Signaling in Neurons
2022 Seed GrantSarah C. Goetz, Ph.D. Duke University Women’s Council Seed Grant Primary cilia are tiny projections from cells that function like an antenna- they receive and may also send…
Erin M. Gibson, Ph.D., Stanford University
Circadian Regulation of Oligodendroglial Senescence and Metabolomics in Aging
2022 Seed GrantErin M. Gibson, Ph.D.Stanford University The brain consists of two main classes of cells, neurons and glia. Glia make-up more than half of the cells in the brain…
Yvette Fisher, Ph.D., University of California, Berkeley
Dynamic Modulation of Synaptic Plasticity During Spatial Exploration
2022 Seed GrantYvette Fisher, Ph.D.University of California, Berkeley The Virginia (Ginny) & Roger Carlson Seed Grant Cognitive flexibility is critical for appropriately adjusting thoughts and behaviors to meet changing demands…
Byoung Il Bae, Ph.D., University of Connecticut
Unique Vulnerability of Developing Human Cerebral Cortex to Loss of Centrosomal Protein
2022 Seed GrantByoung Il Bae, Ph.D.University of Connecticut Carl & Marilynn Thoma Foundation Seed Grant The cerebral cortex is the largest and outermost part of the human brain. It is…