Transplantation of neural progenitor cells has extraordinary potential for the treatment of many nervous system disorders. Several recent studies have shown that progenitor cells derived from the embryonic medial ganglionic eminence (MGE) retain a unique ability to migrate and differentiate into GABAergic interneurons following transplantation into the juvenile or adult rodent brain. We recently demonstrated that these cells are effective in suppressing spontaneous seizures in a mouse model of epilepsy. However, the therapeutic potential of this approach remains largely unexplored for traumatic brain injury, a disorder characterized by interneuron cell loss and a number of health problems linked to neural circuit hyperexcitability (e.g., epilepsy). Here, we propose studies to develop a novel MGE transplantation therapy specifically designed to replace interneurons lost after traumatic brain injury. MGE cells will be transplanted into a widely-used rodent model of closed-head injury at different stages following injury. Our approach involves in vitro patch-clamp recordings, immunofluorescence techniques and neural circuit mapping to evaluate the synaptic integration of MGE- grafted interneurons. A battery of behavioral assays and video-EEG monitoring will also be applied.
Two specific aims are proposed: (i) evaluate the synaptic integration of MGE cells grafted into brain injured hippocampus, and (ii) assess the therapeutic potential of MGE cell grafts in a mouse model of traumatic brain injury. If successful, our results will provide new information about the functional plasticity of MGE progenitors in the injured adult brain and would establish relatively direct proof of concept for interneuron transplantation to treat traumatic brain injury, particularly for conditions where loss of inhibition is a major contributor.
With nearly 6 million Americans living with disabilities resulting from a traumatic brain injury, at an estimated annual cost of $66 billion per year, development of an effective neuron replacement strategy could have enormous impact. The proposed research will develop a cell transplantation procedure to replace a specific type of neuron, cortical interneurons, following experimental head injury. Understanding the therapeutic potential of these newly generated inhibitory neurons is essential before these discoveries can be translated into new therapies for human brain injury.
| Dinday, Matthew T; Girskis, Kelly M; Lee, Sunyoung et al. (2017) PAFAH1B1 haploinsufficiency disrupts GABA neurons and synaptic E/I balance in the dentate gyrus. Sci Rep 7:8269 |
