NO Honey, I Don't Remember

tion that learning is a unitary process and that there Nitric oxide (NO) is a soluble gas that acts as a novel should be a 1:1 correspondence between it and NOStype of intercellular messenger molecule in the brain dependent mechanisms. However, the results of Müller (Bredt and Snyder, 1992). NO has been suggested to in honeybee suggest a different interpretation: that there play a role in learning and memory (Table 1) and in types are multiple, overlapping memory systems, only some of neuronal plasticity thought to contribute to learning, of which involve NO. If these systems are engaged to including both long-term potentiation (LTP) in hippodifferent extents under different circumstances, then incampus and long-term depression (LTD) in cerebellum hibiting NOS may have different effects in different ex(for reviews see Hawkins et al., 1994; Zhuo and Hawkins, periments. Thus, for example, Bannerman et al. (1994a) 1995). However, the involvement of NO in mammalian found that NOS inhibitors block spatial learning in rats learning, LTP, and LTD is controversial (Bannerman et with multiple training trials per day but not with one trial al., 1994a, 1994b; Linden and Connor, 1992), and the per day and concluded that NO is not really involved balance of the evidence has shifted back and forth. In in learning. By contrast, based on similar results on this issue of Neuron, U. Müller (1996) describes expericonditioning in honeybee, Müller concluded that NO is ments in which he took a new approach to this problem involved in only one of several types of learning. A variaby using the honeybee to investigate the function of tion on this pluralistic view is that redundant memory NO. He reports that there are several different memory systems can compensate when the primary system is systems that are engaged by different numbers of trainnot functioning. This idea has received support from ing trials and that cover different (but overlapping) time experiments showing that the delayed learning that ocspans in honeybee. Inhibition of NO synthase (NOS) curs in the presence of NOS inhibitors appears to enduring training blocks only one of these: long-term (24 gage learning systems that are not normally strongly hr) memory following multiple training trials. NOS inhibiengaged (Mogensen et al., 1995a, 1995b). tors have no effect on initial learning or medium-term Unfortunately, the particular pattern of results that (3 or 8 hr) memory and no effect on the modest level of Müller found for conditioning in the honeybee does not long-term memory following a single training trial. Thus, seem to apply generally to other species and tasks; the in honeybee, NO seems to be critically involved in only effectiveness of NOS inhibitors can not in general be one type of memory: long-term memory following reexplained by number of training trials or time between peated training trials. This conclusion is reminiscent of training and testing (Table 1). A more general explanasimilar conclusions about the role of the transcription tory concept might be that the effect of NO depends on factor CREB in long-term memory in Aplysia, Drosophthe pattern of activity in the target neurons, which would ila, and mice (reviewed by Frank and Greenberg, 1994), be different under different behavioral circumstances. and Müller speculates that NO might act via CREB in This idea has received experimental support in vitro honeybee. Consistent with this idea, NO is thought to (Zhuo et al., 1994), but is more difficult to test in vivo. act via CREB in mammalian PC12 cells (Peunova and Another difficulty in testing the role of NO in vivo has Enlikolopov, 1993). been that most NOS inhibitors act not only on neuronal NOS inhibitors have previously been shown to interNOS but also on endothelial NOS, which causes large fere with learning and memory in a variety of other spechanges in blood pressure in vertebrates. This may not cies including rat, chick, rabbit, goldfish, and octopus, be a problem in honeybee, which is not known to have and in a number of tasks, including spatial learning, endothelial NOS. A new inhibitor that is relatively specific social and olfactory memory, passive avoidance, eyefor neuronal NOS has recently been found to produce blink conditioning, vestibular–ocular reflex (VOR) adaplearning deficits in chicks similar to those previously tation, and tactile discrimination (Table 1). In verteobtained with conventional NOS inhibitors, supporting brates, these tasks are thought to be dependent on a role of NO in vertebrate learning (Holscher, 1994). several different brain areas including hippocampus and As in studies of learning, NOS inhibitors have procerebellum. The inhibitor studies have generally induced a mixed pattern of results in studies of LTP in cluded appropriate controls for the specificity of action hippocampus and LTD in cerebellum: the inhibitors of the drugs and for possible effects on processes other block induction but not maintenance, the block is somethan learning and memory, such as sensory capabilities, times partial, and there are reports of failure to produce