Nocturnal motor coordination deficits in neuronal nitric oxide synthase knock-out mice

Abstract

Nitric oxide is formed in the brain primarily by neurons containing neuronal nitric oxide synthase (nNOS), though some neurons may express endothelial NOS (eNOS), and inducible NOS (iNOS) only occurs in neurons following toxic stimuli 4,5,12 Mice with targeted disruption of nNOS (nNOS −) display distended stomachs with hypertrophied pyloric sphincters reflecting loss of nNOS in myenteric plexus neurons. 7 nNOS − animals resist brain damage following middle cerebral artery occlusion 8 consistent with evidence that excess release of nitric oxide mediates neurotoxicity in ischemic stroke. 3 Neuronal NOS − mice have no grossly evident defects in locomotor activity, breeding 10 long-term depression in the cerebellum, 9 long-term potentiation in the hippocampus, 11 and overall sensorimotor function. 10 However, nNOS − animals display excessive, inappropriate sexual behavior and dramatic increases in aggression. 10 Because the cerebellum possesses the greatest levels of nNOS neurons in the brain, it was surprising that presumed cerebellar functions such as balance and coordination were grossly normal in nNOS − mice. These previous studies were all conducted during the day (between 1400 and 1600, lights on at 0700). We now report striking, discrete abnormalities in balance and motor coordination in nNOS − mice reflected selectively at night.