One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was combined with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of calcium-calmodulin-dependent kinase II (CaMKII) resulted in a loss of hippocampal long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit memory task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit memory storage, in a manner that is independent of its potential role in development.

Although long-term potentiation (LTP) in the CA1 region of the hippocampus is initiated postsynaptically by the influx of Ca2+ through N-methyl-D-aspartate receptor channels, the maintenance of LTP seems to be at least in part presynaptic. This suggests that the postsynaptic cell releases a retrograde messenger to activate the presynaptic terminals. It is likely that this messenger is membrane-permeant and reaches the presynaptic neuron by diffusion. We therefore have investigated two major membrane-permeant candidate retrograde messengers, arachidonic acid and nitric oxide (NO). Consistent with arachidonic acid or a lipoxygenase metabolite being a retrograde messenger, the phospholipase A2 and lipoxygenase inhibitor nordihydroguaiaretic acid blocked LTP in the guinea pig CA1 region in vitro. However, arachidonic acid (up to 100 microM) did not reliably produce activity-independent LTP, and activity-dependent potentiation by arachidonic acid was blocked by DL-aminophosphonovaleric acid. Since nordihydroguaiaretic acid also interferes with signal transduction involving NO, we next examined whether inhibitors of NO synthase block LTP. NG-Nitro-L-arginine blocked LTP when given in the bath, and this inhibition was partially overcome by high concentrations of L-arginine, suggesting that the inhibitor is specific to NO synthase. NG-Nitro-L-arginine and NG-methyl-L-arginine (but not NG-methyl-D-arginine) also blocked LTP when injected intracellularly, indicating that NO synthase is located in the postsynaptic cell. The NO, in turn, seems to be released into the extracellular space, since bathing the slice with hemoglobin, a protein that binds NO and is not taken up by cells, also blocked LTP. Moreover, NO enhances spontaneous presynaptic release of transmitter from hippocampal neurons in dissociated cell culture. These data favor the idea that NO might be a retrograde messenger in LTP.

Hippocampal pyramidal cells are called place cells because each cell tends to fire only when the animal is in a particular part of the environment—the cell's firing field. Acute pharmacological blockade of N -methyl- d -aspartate (NMDA) glutamate receptors was used to investigate how NMDA-based synaptic plasticity participates in the formation and maintenance of the firing fields. The results suggest that the formation and short-term stability of firing fields in a new environment involve plasticity that is independent of NMDA receptor activation. By contrast, the long-term stabilization of newly established firing fields required normal NMDA receptor function and, therefore, may be related to other NMDA-dependent processes such as long-term potentiation and spatial learning.

The hippocampal formation is critical for the acquisition and consolidation of memories. When recorded in freely moving animals, hippocampal pyramidal neurons fire in a location-specific manner: they are "place" cells, comprising a hippocampal representation of the animal's environment. To explore the relationship between place cells and spatial memory, we recorded from mice in several behavioral contexts. We found that long-term stability of place cell firing fields correlates with the degree of attentional demands and that successful spatial task performance was associated with stable place fields. Furthermore, conditions that maximize place field stability greatly increase orientation to novel cues. This suggests that storage and retrieval of place cells is modulated by a top-down cognitive process resembling attention and that place cells are neural correlates of spatial memory. We propose a model whereby attention provides the requisite neuromodulatation to switch short-term homosynaptic plasticity to long-term heterosynaptic plasticity, and we implicate dopamine in this process.