White matter tissue Ruxolitinib JAK inhibitor showed a gross decrease in its size, as was observed in sections labeled with myelin basic protein. Observed reduction in the neocortex thickness in P35 PDC-deficient females is consistent with the data from human patients where a gross reduction of cortical tissue and enlargement of lateral ventricles was often found. Neuronal loss combined with gliosis was observed in PDC-deficient female mice in the present study. Furthermore, most of the observed structural abnormalities in the brain of systemic PDC-deficient mice are consistent with the reported pathologies in PDCdeficient patients. Our mice did not exhibit any basal ganglia lesions. This could be due to a milder degree of PDC-deficiency in our female mice. It should be noted that there are differences in the nature and degree of PDC-deficiency in the mouse model and affected patients. In our model with PDC-deficiency in heterozygous female mice only, each cell has either AZD2281 763113-22-0 normal level of PDC activity or no activity at all. In PDC-deficient patients the nature of defect often reduces PDC activity but all cells have the same level of residual activity in male patients and variable level of residual activity in the cells of female patients. Furthermore, all our animals were 35-day-old at the time of pathological analysis whereas the reported PDC-deficient patients had a varying age from infancy to adolescent. These variations make direct comparison difficult to interpret. Two main causes of structural defects of the central nervous system in PDC deficiency have been suggested: developmental malformations and degenerative changes. Congenital developmental malformations have been described for all cases of PDC deficiency which were examined at autopsy, being remarkably less profound in males with early onset of disease. However, destructive neurodegenerative lesions were more often observed in male patients with the early onset of the disease suggesting that in males the primary cause may be reduced cell survival. Prenatal and early imaging in a few cases have suggested that the onset of these neurologic deficits occurs prenatally, however, the timing and pathologic progression are essentially uncharacterized in PDC-deficient patients. Our results also show that cell proliferation and differentiation are impaired in PDC-deficient fetuses. To evaluate the cellular processes responsible for structural abnormalities, we analyzed BrdU incorporation into brain cells prenatally and postnatally using single injection to study cell proliferation and multiple injections with survival of the experimental animals to investigate cell migration and differentiation. The prenatal studies indicated impairment in proliferation of cells on E14 and their subsequent migration and differentiation into mature Purkinje neurons on P5. Studies with postnatally injected BrdU were used to address question whether reduction in cerebellar granule cell volume originated from changes in proliferation and migration processes. Using acute BrdU labeling protocol with P5 mice we found reduction in density of actively proliferating cells. Moreover, the results of chronic BrdU labeling experiment with P5 mice showed increased density of BrdU + cells in the layer intermediate between external and internal granule cell layers. These findings suggest reduced proliferation of granule cells and their delayed migration during the postnatal period. Taken together, the results show that both cell proliferation and differentiation of newly generated precursors into neurons are reduced in PDC-deficient female mice in both the prenatal and early postnatal periods. There was no evidence of gross motor defects in PDC-deficient mice as measured by locomotor activity in a novel environment. PDC-deficient mice had markedly decrease acoustic startle reflexes and demonstrated evidence of impaired PPI.