UCSF

Neocortical inhibitory neurons originate primarily in the ventral telencephalon and migrate tangentially into the dorsal telencephalon. In the postnatal neocortex, inhibitory neurons sculpt information processing and regulate critical periods for experience-dependent cortical plasticity. Remarkably, when transplanted, embryonic inhibitory neurons disperse, survive, and modulate inhibition in the recipient neocortex. Inhibitory neuron transplantation may thus offer a means for modifying neural circuits in the diseased brain. At present, however, little is understood about how these cells develop postnatally, both during normal development and in transplantation scenarios. My dissertation has thus examined the developmental cell death of inhibitory neurons, and the functional contributions of transplanted inhibitory neurons to recipient cortical plasticity. My results define a postnatal period of Bax-dependent developmental cell death, through which 40% of this population is eliminated from the neocortex. When embryonic inhibitory neuron precursors were transplanted during the period of normal recipient cell death, they died when they reached a cell-intrinsic age equivalent to that of endogenous cells during the period of endogenous cell death. Surprisingly, over a range of transplant sizes, the rate of transplant cell death also remained fixed and equal to that of normal endogenous cell death. It thus appears that the timing and extent of inhibitory neuron cell death are intrinsically determined, and free from competitive influences. This feature allows the neocortical inhibitory population to be significantly expanded by transplantation. In collaboration with Sunil Gandhi and Michael Stryker, I examined whether transplanted inhibitory neurons alter cortical plasticity in the recipient neocortex. Remarkably, transplanted inhibitory neurons induced cortical plasticity during a brief period, again when they reached a cell-intrinsic age equivalent to that of endogenous inhibitory neurons at the peak of the normal critical period. Thus, it appears that both inhibitory neuron developmental cell death, and the critical period, could reflect the execution of cell intrinsic developmental programs in inhibitory neurons. Surprisingly, transplanted inhibitory neurons retain and execute these developmental programs in the recipient brain. These findings provide fundamental insights into the nature of inhibitory neuron development and transplantation, ones that will guide the development and therapeutic application of inhibitory neuron transplantation strategies.