Table 1.

Physiologic roles of tPA in the CNS

	Biologic process	Method	Effect	References
CNS development	Survival	Genetic deletion studies	Non essential role of tPA during embryonic development	69,71
	Neuronal migration	Ex vivo studies of tPA−/− mice and controls using cerebellar slice technology	Perturbed migration of cerebellar granule neurons in tPA−/− mice	75
	Neuronal remodeling	In vitro studies of neuroblastoma clonal cell lines and neural progenitor cell	tPA is released in the neuronal growth cone where it might affect neurite outgrowth and remodeling	73,74
	Cerebrovascular development	Immunohistochemical and confocal microscopy studies in tPA−/− and control murine brains	Reduced number of vascular smooth-muscle cell covered, large diameter vessels and increased junctional localization of tight junction protein ZO1 in tPA−/− mice	76
	Cerebroventricular development	In vivo MRI and immunohistochemical/confocal microscopy studies in tPA−/− and control mice	Mild cerebral ventricular malformations and distorted ependymal lining in tPA−/− mice	76
Adult CNS physiology	Learning and memory	Expression analysis and experimental in vivo models of learning/memory in tPA−/−, tPA overexpressor and control mice	Learning and memory is significantly decreased in tPA−/− mice whereas overexpression of tPA facilitates learning	4,36,80,81,82,83,85,86
	Neurovascular coupling	In vivo models of whisker evoked neuronal activation in tPA−/− mice. Immunohistochemical/confocal microscopy studies and in vitro/in vivo effects of tPA on blood vessel tone	Neurovascular coupling is perturbed in tPA−/− mice. tPA is expressed in vasoactive interneurons and might regulate vascular tone.	7,20,93
	Neurometabolic effects	In vitro neuronal cultures	tPA increase neuronal uptake of glucose	29,95
	Vascular permeability	In vitro and in vivo studies	tPA increase permeability of the BBB through interaction with the NVU.	14,15,16,99,135