Subtle changes in synaptic transmission are likely responsible for learning and memory, but the molecular cast of characters at play in this complex process is only partly known. Two papers in this week's Nature Neuroscience online introduce two new players, and quite distinct ones at that. As it turns out, the transcription factor NF-κB and the neuronal calcium sensor-1 both can have profound effects on synaptic plasticity by modulating neuronal signaling.
NF-κB is famous for its involvement in immune responses, yet even in the early '90s, Kaltschmidt et al. spotted it in synaptosomes in a complex with its inhibitory subunit IκB. This finding raised the intriguing possibility that activation of this transcription factor at nerve endings leads to its delivery to the nucleus, where it could modify gene transcription. Now, principal investigator David Baltimore at the California Institute of Technology, Pasadena, with colleagues there and at the University of California at Los Angeles, shows that this is indeed what happens.
First author Mollie Meffert and coworkers followed the fate of activated NF-κB by coupling its p65 subunit to green fluorescent protein (GFP). Meffert expressed this chimera in cultured hippocampal neurons and used its fluorescence as a tracer. To see if the protein is retrogradely transported to the nucleus from dendrites, the authors bleached the fluorescence in a small section of a dendrite and then measured its recovery. She found that the green chimera diffused into the bleached section only from the distal, outer end of the dendrite. Importantly, this diffusion was rapidly accelerated by stimulating the neurons with glutamate or N-methyl-D-aspartate, indicating that neuronal signaling drives the transport of NF-κB toward the nucleus.
The authors then tested the physiological relevance of NF-κB in vivo by looking at the behavior of p65-deficient mice. In a radial arm maze, where animals are trained to find a food treat at the end of every arm, mice lacking the NF-κB subunit were more likely to waste time revisiting previously harvested arms. After two days of trials, the NF-κB-negative mice visited food-containing arms about 20 percent of the time, vs. 40 percent for wild-type animals. After eight days, the difference was no longer significant, indicating that the deficient mice do learn, albeit more slowly.
The researchers further report that NF-κB can be activated in neurons by Ca2+, and that this requires the activity of the calcium-dependent kinase CaMKII. In the second Nature Neuroscience paper, principal author Felix Schweizer, also at the University of California at Los Angeles, together with colleagues at UCLA and at Baylor College of Medicine, Houston, Texas, show that another calcium-binding protein, neuronal calcium sensor-1 (NCS-1), plays an important role in short-term synaptic plasticity.
Short-term synaptic plasticity is often measured as the change of postsynaptic transmission that follows repeated stimulation. This can be either an increase (facilitation) or a decrease (depression) in the strength of the postsynaptic current. By stimulating one of a pair of connected hippocampal neurons and measuring the current elicited in the other, first author Tanya Sippy and colleagues tested the effect of NCS-1 on synaptic plasticity. Sippy found that in normal cells, a second stimulus results in depression—the amplitude of the induced second current being about half that of the first. But when the authors transfected cells with low amounts of NCS-1, the plasticity reversed—now, the second stimulus resulted in facilitation, inducing almost twice as much current in the postsynaptic neuron as the first stimulus. Importantly, Sippy found that NCS-1 infected cells had the same basal level of synaptic transmission as wild-type cells.
These findings address one of the most debated questions about short-term plasticity, namely whether it is a function of preexisting synaptic strength. Sippy's findings suggest that it is not, as NCS-1 does not alter basal levels. But what exactly is the role of this calcium binder? Most models conceived to explain facilitation require that calcium released from previous stimulations remains in the presynaptic terminal, so that upon subsequent stimulation it will bolster the release of neurotransmitters at the synapse. But as NCS-1 binds calcium, it is not likely to contribute to the buildup of the free cation. More recently, Blatow et al. have suggested that buffers in the presynaptic terminal may be responsible for facilitation. Although such chelators could mop up Ca2+, Blatow suggests that they are easily saturated; thus, subsequent stimuli evoke more synaptic activity because the release of calcium overwhelms the buffering capacity.
Could NCS-1 be such a buffer? Probably not, suggest Sippy and colleagues, because then it would be expected to affect basal transmission, but the authors found it does not. Instead, they suggest that NCS-1 functions as a "release sensor," which, in cooperation with other unidentified molecules, can raise presynaptic calcium levels.
Perhaps most significant is the suggestion that neurons can alter their plasticity quite dramatically by merely modifying the expression of NCS-1. In this regard, it is worth noting that the protein has been shown to be upregulated in the prefrontal cortex of schizophrenic and bipolar patients.—Tom Fagan
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