When young inhibitory interneurons are transplanted into the brains of older mice, they integrate into the host brain and can lead to significant changes in how the host brain functions. Such transplants have therapeutic benefits in mouse models of Alzheimer's disease, epilepsy, Parkinson's disease, neuropathic pain, schizophrenia, amblyopia, and stroke. Understanding how the transplanted cells cause these benefits is essential to knowing whether interneuron transplant based therapies could benefit humans, and may also reveal ways in which medications could lead to the same symptom improvements. Transplanting interneurons into the visual cortex of mice creates a one week window of heightened brain plasticity, during which temporary changes in visual inputs lead to permanent changes in the neurons' visual responses. Such large-scale plasticity is normally only possible during a brief ?critical period? in development. Interneuron transplantation is the only known way to reopen the critical period after it has closed, and thus provides a unique opportunity to study the underpinnings of brain plasticity. In this proposal, I will define the mechanisms by which transplanted interneurons create new critical periods. First, I will transplant interneurons into visual cortex and assess their maturation using simultaneous whole-cell recordings of the transplant-derived interneurons and their synaptic targets (Aim 1). This will reveal what changes in interneuron physiology and synaptic outputs allow entry into, and exit from, critical periods, isolated from the substantial changes in excitatory function and brain wiring that are normally coincident with interneuron development. Next, I will use genetic techniques to interrupt the synaptic communication of transplanted interneurons with host neurons at specific times during development. This will allow me to determine whether the synaptic outputs of interneurons are necessary either for causing critical periods, or for maintaining the changes in cortical responses that are induced during critical periods (Aim 2). Finally, I will transplant interneurons into the auditory cortex, where a critical period occurs earlier, to see whether the mechanisms by which transplants induce critical periods are generalizable across cortices (Aim 3). The outcomes of these studies are of immediate relevance to epilepsy, a disease of aberrant plasticity for which current best medical and surgical therapies still leave 30-40% of patients with ongoing seizures. I am an epileptologist with prior experience using electrophysiology and imaging techniques to study circuits in slices of the hippocampus, another brain region prominently involved in epilepsy. In addition to the scientific output of this proposal, these experiments will allow me to learn in vivo recording of single or large groups of neurons, immunohistochemistry, and cell transplantation, techniques that I will continue to use throughout my scientific career. During the period of this grant, I will be mentored by Drs. Andrea Hasenstaub, Michael Stryker, and Christoph Schreiner. The results of these proposed aims will form the basis of my future independent investigations into how interneuron-induced plasticity can be translated into clinical therapies.
The brain is only minimally able to rewire after childhood. This research explores how adding younger brain cells can allow adult brains to make the sort of drastic changes in connections that are normally only possible during childhood. Understanding how young cells can change the established circuits in adult brains could allow new treatments in epilepsy and psychiatric disease.
