Understanding G-protein signaling is important for appreciating the role of RGS14 in learning and memory. G-proteins are heterotrimeric switches that are involved in regulating an array of cell-signaling pathways . Downstream signaling pathways include: activation or inhibition of adenylyl cyclase, opening or closing of K+ channels, phospholipase C activation, and cGMP phosphodiesterase activation  (See original figure 1). Along with calcium and Ras/MAP kinases, G-protein signaling is one of the key regulators of LTP. On one had there are excitatory G-protein signals such as those from the Gs and Gq families of G-proteins that keep voltage-gated M-type K+ channels closed in neurons (n.b. Gs activates adenylyl cyclase and Gq activates phospholipase C) [5, 6]. On the other hand there are inhibitory G-protein signals downstream of the Gi and Go pathways, which include voltage-gated Ca2+ channel inhibition and activation of inwardly rectifying K+ channels [7, 8].
Although the effect of the neuron’s electrochemical gradient by Gi and Go is the opposite of Gs and Gq G-proteins, Gi and Go do not directly regulate the function of Gs and Gq G-proteins. That is to say, they do not put the brakes on each other; they only impose opposite electrical properties onto the neuron. Thus, without brakes, both signaling pathways have the potential to spiral out of control. RGS Proteins (known Regulators of G-protein Signaling) modulate G-protein signaling so this doesn’t happen. Typically RGS proteins do this by limiting G-Protein activation by acting as GTPase activating proteins (GAP). RGS14 is one such RGS protein that is uniquely positioned to decrease G-protein excitatory mechanisms and promote inhibitory mechanisms, making it an ideal for regulation of synaptic plasticity. RGS14 limits the lifetime of the Gα subunit, in this way it suppresses excitatory pathways more so than inhibitory pathways because Gi activity is regulated largely by the Gβγ G-protein subunit. Furthermore, RGS14 can actually act as a scaffold to assemble Gαi subunits.
Knowing this, Lee et al., performed a series of experiments aimed at elucidating the role of RGS14 in hippocampal LTP, plasticity, and memory formation. Several forms of learning and memory have been extensively studied as LTP forming at the DG-CA3-CA1 hippocampal sub-region circuit. Oddly, a well defined fourth region, the CA2 sub-region of the hippocampus, has not been shown to be involved in this circuit. The neurons in the CA2 region don’t seem to have LTP abilities. Lee et al., using monoclonal antibodies to select for RGS14 (through immunohistochemical staining) revealed that there were high densities of RGS14 found in CA2 pyramidal neurons. Next, they compared the CA2 LTP abilities of RGS14 knock-out mice to that of wild-type mice. Synaptic stimulation results in sustained LTP in CA1/CA3 neurons of wild-type rodents, however, not in the CA2 region as expected. Interestingly, the RGS14 knock-out mice showed synaptic plasticity in all three hippocampal CA regions!
Next, Lee et al. investigated the underlying molecular mechanisms as to how the loss of RGS14 affords the CA2 region the opportunity to form LTP. Along with its GAP activity, RGS14 is known to bind several proteins such as Raf kinases, leading to the inhibition of growth factor-directed MAP kinase signaling. Therefore, they tested whether an inhibitor of ERK/MAP kinase would affect the newly endowed increased capacity for LTP in CA2 neurons caused by the loss of RGS14. The MEK inhibitor used in the study completely eliminated the LTP potential in CA2 neurons (It was also able to eliminate the LPT capacity in the CA1 region). This suggests that MEK/ERK pathways play a key role in regulation of LTP and RGS14 subserves this signaling pathway in the CA2 region of the hippocampus.
Finally, the experimenters tested learning and memory performance in the RGS14-KO mice. They found that the loss of RGS14 actually improved the performance of these mice in tests of novel object recognition and spatial memory. Meanwhile it did not enhance the performance of any non-hippocampal-dependent tasks. This suggests that inhibitors of RGS14 could potentially serve as treatments for cognitive deficits associated with various forms of disease/disorders such as Alzheimer’s or Fetal Alcohol Syndrome, which have symptoms known to affect hippocampal learning and memory. One caveat to this notion of trying to increase LTP capacity however, is that unbridled synaptic potentiation is what leads to epileptic seizures. Thus, as another old adage of all scientists goes, “More research is needed.”
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