They AZD9291 concentration report a nearly 4-fold increase in
the basal expression level of dCREB2-b as compared to wild-type animals. This increase in dCREB2-b expression is also observed in individual wild-type brains cultured in Mg2+-free medium, indicating that increases in calcium influx in the absence of a Mg2+ block can directly lead to increased levels of dCREB2-b. If the absence of the Mg2+ block directly affects the expression of the dCREB2-b repressor, then the expression of CREB2-target genes should be affected. The authors tested this hypothesis by examining expression levels of the genes activin, staufen, and homer, previously shown to be transcriptionally induced after spaced training ( Dubnau et al., 2003). Remarkably, Miyashita et al. (2012) observed an absence of this upregulation in dNR1(N631Q) flies. The block in gene induction was cell autonomous: flies expressing
dNR1(N631Q) in mushroom body neurons showed no increase in homer expression in mushroom bodies but still displayed homer upregulation in other structures such as the protocerebral bridge. Miyashita et al. (2012) conclude that decreased transcription of LTM-induced genes is a result of increased dCREB2-b repressor activity in dNR1(N631Q)-expressing neurons ( Figure 1). Wild-type flies forced to express dCREB2-b at similarly elevated levels also display a block in activity-dependent transcription of activin, staufen, and homer. Thus, dCREB2-b levels are enhanced by removal of the Mg2+ block and this enhancement selleck inhibitor is sufficient to mimic the observed memory phenotypes of flies expressing the dNR1(N631Q) mutant NMDAR. It is curious that these conclusive experiments on the role of coincidence detection by NMDARs have been conducted in Drosophila, which, like other insects, uses acetylcholine (Ach) as its major excitatory neurotransmitter. Indeed, one may ask, how does the NMDAR function in nonglutamatergic synapses? Although Drosophila NMDARs differ from mammalian NMDARs in their cytoplasmic domains, they are functionally similar to their mammalian homologs in terms of conductance and gating. We suggest that
unlike mammalian central synapses in which AMPA-type glutamate receptors mediate postsynaptic depolarization, GBA3 nicotinic acetylcholine receptors mediate depolarization in Drosophila synapses. Glutamate required for NMDAR activation could conceivably be released by a distinct, temporally coupled glutamatergic neuron. Alternatively, it may be coreleased by the presynaptic cholinergic neuron. Consistent with this idea, glutamate corelease is widely documented in the mammalian CNS and has been recently proposed as a contributing mechanism for plasticity in the Drosophila antennal lobe ( El Mestikawy et al., 2011; Das et al., 2011). Thus, the NMDARs’ ability to function as a coincidence detector may have led to its widespread use for Hebbian synaptic plasticity in both glutamatergic and nonglutamatergic systems ( El Mestikawy et al., 2011).