ALTERATION OF NEURONAL NITRIC-OXIDE SYNTHASE ACTIVITY AND EXPRESSION IN THE CEREBELLUM AND THE FOREBRAIN OF MICROENCEPHALIC RATS

Microencephalic rats were obtained through gestational (for the forebr ain) or neonatal (for the cerebellum) administration of the DNA-alkyla ting agent methylazoxymethanol acetate (MAM), which selectively kills dividing cells during neurogenesis. In the microencephalic cerebellum the specific activity of calcium-dependent nitric oxide synthase (NOS) was decreased by 35-40% at 12, 28 and 70 days of age. Other neurochem ical markers not related to granule cells (the neuronal population sel ectively compromised by neonatal MAM treatment), choline acetyltransfe rase (ChAT) and glutamate decarboxylase (GAD) were not decreased, but actually increased when determined as specific activity. In agreement with the decreased catalytic activity measured in the tube, the expres sion of neuronal NOS protein was attenuated as judged from immunohisto chemistry and Western blotting. In the microencephalic forebrain, the specific calcium-dependent NOS activity measured in homogenates of the whole hemisphere was significantly increased as compared to normal an imals. Accordingly, immunohistochemistry for neuronal NOS, as well as NADPH-diaphorase histochemistry revealed an apparent increase in the d ensity of strongly reactive neurons in the underdeveloped cortex and s triatum of microencephalic rats. The results reported here demonstrate that permanent alterations of neuronal NOS activity and expression oc cur when the development of the brain and its neuronal circuits are se verely compromised. Furthermore, the permanent downregulation of neuro nal NOS in the cerebellum of microencephalic rats may be exploited for the study of the role of NO in mechanisms of synaptic plasticity such as long term depression (LTD). (C) 1998 Elsevier Science B.V. All rig hts reserved.