AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing.

Voltage-gated sodium channels (NaCh) are colocalized with isoforms of the membrane-skeletal protein ankyrinG at axon initial segments, nodes of Ranvier, and postsynaptic folds of the mammalian neuromuscular junction. The role of ankyrinG in directing NaCh localization to axon initial segments was evaluated by region-specific knockout of ankyrinG in the mouse cerebellum. Mutant mice exhibited a progressive ataxia beginning around postnatal day P16 and subsequent loss of Purkinje neurons. In mutant mouse cerebella, NaCh were absent from axon initial segments of granule cell neurons, and Purkinje cells showed deficiencies in their ability to initiate action potentials and support rapid, repetitive firing. Neurofascin, a member of the L1CAM family of ankyrin-binding cell adhesion molecules, also exhibited impaired localization to initial segments of Purkinje cell neurons. These results demonstrate that ankyrinG is essential for clustering NaCh and neurofascin at axon initial segments and is required for physiological levels of sodium channel activity.

Nitric oxide facilitates long-term potentiation, but not long-term depression.

Reports that nitric oxide synthase (NOS) inhibition prevents the induction of long-term potentiation (LTP) have been controversial. Recent evidence suggests that NO may help to regulate the threshold for LTP induction. We have tested this hypothesis by examining the effects of stimulus frequency and train duration on synaptic plasticity in the presence of either NO donors or NOS inhibitors. Two different NO donors facilitated LTP induction by stimuli that normally produced only short-term potentiation, whereas NOS inhibitors blocked LTP to stimuli that normally produce small LTP. NO donors facilitated LTP induction even when NMDA receptors were blocked, indicating that NO need not act via NMDA receptors. NO donors and NOS inhibitors were without effect on long-term depression (LTD), suggesting that they act on a distinct potentiating mechanism. Thus, NO could contribute to the establishment of plasticity under physiologically relevant conditions by selectively increasing the probability of LTP induction.

Nitric oxide synthase inhibitors block long-term potentiation induced by weak but not strong tetanic stimulation at physiological brain temperatures in rat hippocampal slices.

Nitric oxide synthase (NOS) inhibitors have been shown to block long-term synaptic enhancements in the mammalian hippocampus. This effect has been somewhat controversial, however, showing sensitivity to both temperature and stimulus strength. We have demonstrated a differential effect of the NOS inhibitor L-NG-nitroarginine (NOArg) on long-term potentiation (LTP) induced by weak and strong tetanic stimulation in slices of rat hippocampus. NOArg prevented LTP induction by a weak tetanus that produced stable potentiation in control slices, while the NOS inhibitor was without effect when strong tetani were used. These results suggest that nitric oxide (NO) produced as a result of tetanic stimulation plays a role in adjusting the threshold of LTP induction, but is not necessary for establishing synaptic enhancement under conditions of strong synaptic activation.