Proper wiring of neuronal circuits during development leads to the establishment of highly effective networks that underlie learning, memory and cognition. It is becoming clear that many neurological disorders, such as autism spectrum disorders, and potentially some neuropsychiatric diseases may in part be caused by irregular circuit wiring. Identifying and understanding the role that specific genes play in the developmental wiring of neuronal networks is a first step towards generating therapies and treatments to cure such disorders. This proposal will examine how one gene, cpg15, is involved in this process. Specifically, it will test whether cpg15 is required for activity-dependent stabilization of synapses and dendrites during neuronal circuit formation in the developing visual cortex of a cpg15 knockout mouse. Extensive literature exists documenting the development of the visual system in mice making it a useful model for circuit formation. Defects in synaptic and dendritic stabilization will be examined using electrophysiology to measure parameters of synapse function. During recording, neurons will be filled with the small diffusible molecule, biocytin, allowing for later reconstruction and analysis of their dendritic arbors. Circuit plasticity, an assay for effective wiring will be assessed in the developing cpg15 knockout mouse by performing monocular deprivation, a classical method for manipulating sensory experience to induce changes in visual system wiring. These changes will be assayed by optical intrinsic signal imaging to measure cortical responsiveness to the deprived and open eyes after monocular deprivation. This proposal will also test whether rescue of cpg15 expression using lentiviral-mediated gene transfer is sufficient to rescue deficient experience-dependent plasticity and defects in synapse and arbor stabilization in cpg15 knockout mice. Since CPG15 is a secreted, extracellular molecule it may have therapeutic potential for rescuing circuit wiring deficits regardless of their etiology. Many neurological disorders, including autism, may be caused by abnormal wiring of the brain's circuits. Identifying genes involved in the developmental wiring of the brain, such as the gene cpg15, and understanding how they work is key to developing effective treatments to cure these disorders.
| Leslie, Jennifer H; Nedivi, Elly (2011) Activity-regulated genes as mediators of neural circuit plasticity. Prog Neurobiol 94:223-37 |
