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.

Site-specific effects of intracerebral injections of three neurokinins (neurokinin A, neurokinin K, and neurokinin gamma) on the expression of male rat sexual behavior.

Accumulating evidence indicates that neurokinins play a role in the neural regulation of male rat copulatory behavior. We have previously reported that injections of the neurokinin substance P into the medial preoptic nucleus facilitated male rat copulatory behavior. Recently, a number of other neurokinins, neurokinin K (neuropeptide K), neurokinin A (substance K), and neurokinin gamma (derived from the same gene as substance P), have been identified in the mammalian CNS. Therefore, in a series of experiments we examined the effects on male copulatory behavior following bilateral injections of different doses of neurokinin K (NkK), neurokinin A (NkA), or neurokinin gamma (Nk gamma) into the medial preoptic area (MPOA), bed nucleus of the stria terminalis (BnST), or the caudate/putamen. Bilateral injections of NkK into the MPOA or BnST inhibited the expression of male copulatory behavior. The most marked effect was seen following bilateral injections of 0.25 and 0.52 nmol of NkK into the MPOA and the BnST. These injections produced a dramatic suppression of copulatory behavior in previously sexually vigorous male rats when compared to control injections. In contrast, bilateral injections of three different doses of NkA into the MPOA failed to affect any parameter of male copulatory behavior. Bilateral injections of 0.431 nmol of Nk gamma into the MPOA failed to affect the expression of copulatory behavior, but significantly delayed its initiation when compared to controls. Bilateral injections of 0.251 nmol of NkK into the caudate/putamen had no significant effect on copulatory behavior in sexually vigorous male rats when compared to control injections. The results of the present study provide further support for a role of neurokinins in the regulation of copulatory behavior in male rat. Taken together, these results suggest that the effects of neurokinins upon the expression of male copulatory behavior are site specific for brain regions in the sexually dimorphic vomeronasal pathway which includes the MeA, BnST, and MPOA.

Ibotenic acid-induced lesions of the medial zona incerta decrease lordosis behavior in the female rat.

To examine the role of the medial zona incerta (mZI) in female sexual behavior, ovariectomized estrogen- and progesterone-treated female rats were tested for sexual receptivity after bilateral injections of the selective neurotoxin ibotenic acid (3 micrograms/0.3 microliter) directly into the mZI. These injections produced a significant attenuation of lordosis behavior in highly receptive females when compared with saline-injected controls. This decrease in sexual receptivity was also reflected in a significant increase of rejections of male mount attempts. However, these lesions did not abolish the display of lordosis behavior. In addition, the frequency of hopping and darting was decreased in ibotenic acid-injected females when compared with controls. Consistent with previous studies, these lesions also produced a transient impairment of drinking behavior (hypodipsia) typical of rats with large electrolytic lesions of the mZI. This study demonstrates that mZI neurons play a role in mediating sexual receptivity in the female rat. Collectively, these results suggest that in addition to the projection from the ventromedial nucleus of the hypothalamus to the midbrain central gray, the functional integrity of the mZI is of crucial importance for the expression of sexual receptivity in the female rat.