The noncompetitive antagonists of the vertebrate NMDA receptor dizocilpine (MK 801) and phencyclidine (PCP), delivered in food, were found to induce a marked and reversible inhibition of locomotor activity in Drosophila larvae. To determine the site of action of these antagonists, an in vitro preparation of the Drosophila third-instar larva was used, preserving the central nervous system and segmental nerves with their connections to muscle fibers of the body wall. Intracellular recordings were made from ventral muscle fibers 6 and 7 in the abdominal segments. In most larvae, long-lasting (>1 h) spontaneous rhythmic motor activities were recorded in the absence of pharmacological activation. After sectioning of the connections between the brain and abdominal ganglia, the rhythm disappeared, but it could be partially restored by perfusing the muscarinic agonist oxotremorine, indicating that the activity was generated in the ventral nerve cord. MK 801 and PCP rapidly and efficiently inhibited the locomotor rhythm in a dose-dependent manner, the rhythm being totally blocked in 2 min with doses over 0.1 mg/mL. In contrast, more hydrophilic competitive NMDA antagonists had no effect on the motor rhythm in this preparation. MK 801 did not affect neuromuscular glutamatergic transmission at similar doses, as demonstrated by monitoring the responses elicited by electrical stimulation of the motor nerve or pressure applied glutamate. The presence of oxotremorine did not prevent the blocking effect of MK 801. These results show that MK 801 and PCP specifically inhibit centrally generated rhythmic activity in Drosophila, and suggest a possible role for NMDA-like receptors in locomotor rhythm control in the insect CNS (Cattaert, 2001)
To determine whether the cloned dNR1 and dNR2 subunits associate to form functional ionotropic receptor channels, they were coexpressed in Xenopus oocytes and the resulting electrophysiological properties were examined. Coexpression of dNR1 and dNR2-2 induced robust NMDA-selective responses, whereas dNR2-1 in combination with dNR1 induced no NMDA-dependent responses in oocytes, suggestive of some functional difference between the two dNR2 isoforms. Coexpression of dNR1 and dNR2-3 has not been tested yet. The oocytes, expressing both dNR1 and dNR2-2, exhibited significant inward currents upon application of NMDA but not AMPA, and the NMDA-activated responses were concentration dependent. This suggests that dNR1 and dNR2 can form a functional ion channel in oocytes, which selectively responds to NMDA. Mammalian NMDA receptors are modulated by glycine (Kleckner, 1998). This also is the case for fly NMDA receptors, although application of glutamate in the presence of glycine appears much less effective than NMDA alone, which may reflect the facts that the relevant structural domains for glycine and glutamate binding are not completely conserved in dNR1 and dNR2 or that residual glycine may alter the response in this heterologous system. Mammalian NMDA receptors are activated by L-aspartate as well as glutamate (Patneau, 1990). Consistent with this observation, fly NMDA receptors are activated by various concentrations of aspartate. When expressed in oocytes, however, conductance through fly NMDA receptors is not voltage dependent. Consequently, dNR1 and dNR2 was also coexpressed in Drosophila S2 cells, thereby revealing a voltage-dependent conductance that is blocked by external Mg2+. Thus, this eletrophysiological profile of coexpressed dNR1 and dNR2 reveals most of the distinguishing characteristics of vertebrate NMDARs (Xia, 2005).
To examine expression of the dNR1 protein, a rabbit anti-dNR1 polyclonal antibody was generated. The antibody recognized a single protein of the appropriate size on Western blot. dNR1 seems to be weakly expressed throughout the entire brain (see dNR1 and dNR2 protein expression in the adult brain). Higher expression levels were observed in some scattered cell bodies and part of their fibers, including those from several pairs of DPM (dorsal-posterior-medial) neurons surrounding the calyx, DAL (dorsal-anterior-lateral) and DPL (dorsal-posterior-lateral) neurons in the lateral protocerebrum (LP), VAL (ventral-anterior-lateral) neurons in the anterior protocerebrum, and two pairs of VP (ventral-posterior) neurons in the posterior protocerebrum. Many cell bodies in the optic lobes also were labeled preferentially. Notably, punctuate staining was detected in many brain regions including the superior medial protocerebrum, suggesting synaptic localization of dNR1 (Xia, 2005).
The anti-dNR1 antibody does not preferentially label MB neurons. This is notable because MBs are critically required for olfactory learning. Instead, preferential dNR1 expression was detected in 12 pairs of cell bodies surrounding the MB calyx. Interestingly, a pair of DPM2 (dorsal-paired-medial 2) neurons are located just next to the previously identified DPM neurons in which no dNR1 expression is detectable. The DPM neurons innervate all the MB lobes and appear involved in early memory. Three additional pairs of DPM3 neurons with cell bodies smaller than DPM2 also showed strong immunolabeling. The spatial distributions of these neurons are highly symmetrical. Four other DPM4 neurons are located medially to the MB calyx and send descending fibers along a common tract. DPM4 neurons are clustered together in some flies but scattered in others. Another two pairs of neurons, DPM5 and DPL (dorsal-posterior-lateral), are located above the MB calyx. They appear to project descending fibers together with DPM4 neurons . The cell bodies of the VP (ventral-posterior) neurons are located beneath the MB calyx. DAL (dorsal-anterior-lateral) neurons are located in the LP region. LP receives extensive olfactory projections through the antennalglomerular tract of the antennal lobe, which itself receives olfactory input from antennae. The function of LP in olfaction and olfactory learning is largely unknown. dNR1 appears only weakly expressed in antennal lobes and central complex (Xia, 2005).
One of the mouse monoclonal anti-dNR2 antibodies allowed evaluation of the distribution of dNR2 proteins in adult brain. This antibody labels two bands with molecular weights close to the deduced sizes of dNR2 proteins. Similarly to dNR1, weak expression of dNR2 was detected in most, if not all, brain neurons. Again, preferential expression was found in several pairs of large neurons. Notably, dNR1 and dNR2 colocalized in four cell bodies of DPM4 neurons. Both proteins also colocalized in many synapse-like punctuate structures including those along the fibers of DPM4 neurons. Nevertheless, not all dNR1-positive neurons appear to express dNR2 at equivalent levels or verse visa. dNR2 is strongly expressed in a pair of DAL2 neurons and two pairs of VAL2 neurons, for instance, whereas dNR1 is strongly expressed in DAL and VAL neurons. These observations suggest that NR1 and NR2 may be regulated differentially during development or by experience or that these subunits may partner in vivo with other unknown subunits to form functional NMDARs (Xia, 2005).
The 3D staining patterns of dNR1 and dNR2 were superimposed into a volume model of adult fly brain to analyze NR-positive fibers in more detail. VAL appears to be the only neurons sending dNR1-positive projections to the front of contralateral MB calyx. Remarkably, all other NR-positive neurons do not appear to send projections to MBs. DPL and DPM5 are descending neurons and project in parallel with DPM4 neurons to the ventral-posterior ipsilateral protecerebrum and then extend anteriorly. The NR-positive fibers from other neurons surrounding the MB calyx do not enter the calyx or lobes of MBs. This, however, does not exclude the possibility that they may contact MBs through presynaptic fibers where no dNR proteins are expressed. DAL projects ascending fibers toward the superior medial protocerebrum with dNR1 protein distributed at the cell bodies and synapse-like puncta along its fibers. Thus, at least in DAL neurons, dNR1 appears to localize both pre- and postsynaptically (Xia, 2005).
The dNR1 gene consists of 15 exons scanning more than 24 kb of genomic DNA. The 5′ end overlaps with Itp-r83A, the fly homolog of an inositol 1,4,5-tris-phosphate receptor. Flies homozygous for an F-element insertion in the third intron of dNR1 are subviable and female-sterile. Two independent EP element insertions also lie in dNR1 or nearby. EP3511 inserts in the first intron of the dNR1 gene, 718 bp upstream of the start codon in exon 2. EP331 is inserted 425 bp downstream of the 3′ end of the dNR1 transcription unit. Expression levels of dNR1 protein are reduced but not eliminated in homozygous EP3511/EP3511 or EP331/EP331 flies, indicating that both EP insertions represent hypomorphic mutations of dNR1. EP3511/EP3511 or EP331/EP331 homozygotes are viable, which allowed evaluation olfactory learning. Compared to wild-type flies, learning was reduced in both homozygotes (Xia, 2005).
The learning defects of EP3511 or EP331 mutants were rescued by cosmids containing genomic DNA from the dNR1 region. Cosmid-A contains the full-length Itp-r83A coding sequence and upstream elements that include only partial coding sequence of dNR1. Conversely, Cosmid-B and Cosmid-C contain all of the dNR1 transcription unit and only part of Itp-r83A. Cosmid-A, but not Cosmid-B or Cosmid-C, rescues the lethality associated with two different mutations of Itp-r83A, whereas Cosmid-B and Cosmid-C, but not Cosmid-A, rescued the learning defect of the EP3511 and EP331 mutants. These results establish that the learning defects of the EP mutants are due to disruption of the dNR1 gene not the Itp-r83A gene (Xia, 2005).
EP331 also allowed the use the EP-element to control the expression of dNR1 conditionally. The EP element in EP331 flies is inserted downstream of, and in an opposite orientation to, the transcription start site of dNR1. When combined with a GAL4 driver, this EP element yields an antisense transcript of dNR1. In transheterozygous EP331/+, hs-GAL4/+ flies, an anti-dNR1 message was induced by heat shock and was still detected 15 hr later, leading to a significant reduction in dNR1 protein. This antisense message was also detected before heat shock in EP331/+, hs-GAL4/+ flies but absent in heterozygous EP331/+ flies, suggesting some leaky expression of hs-GAL4 was driving low-level expression of anti-dNR1. This leaky expression did not produce any measurable effect on NR1 protein levels from Western blot analysis (Xia, 2005).
The disruption of dNR1 in EP331/+, hs-GAL4/+ flies was further confirmed with immunohistochemistry. Anti-dNR1 immunostaining was diminished throughout the entire brain after heat shock as compared with no heat shock. This reduction in dNR1 was quantified in a pair of dorsal-anterior-lateral (DAL) and a pair of ventral-anterior-lateral (VAL) neurons, where the protein is expressed at high levels. In both DAL and VAL neurons, the immunofluorescence intensity was reduced significantly 15 hr after heat shock (Xia, 2005).
Accordingly, learning was severely disrupted 15 hr after heat shock. In contrast, learning was disrupted only mildly in EP331/+, hs-GAL4/+ flies in the absence of heat shock. This mild disruptive effect is consistent with the observation that hs-GAL4 yields some leaky expression of anti-dNR1 message through development, though a concommitant reduction in NR1 protein was not detected. Alternatively, this transgenic line might harbor slight, nonspecific differences in genetic background (Xia, 2005).
Whether dNR1 was required for long-lasting memory produced by extended training was evaluated. EP331/+, hs-GAL4/+ flies were subjected to spaced or massed training 15 hr after heat shock and then tested for 1-day memory. In the absence of heat shock, 1-day memory after both spaced and massed training was normal. When trained 15 hr after heat shock, 1-day memory after massed training was normal, whereas that after spaced training was significantly reduced. Typically, 1-day memory after spaced training is composed of 50% LTM and 50% ARM (Anesthesia-Resistant Memory), and LTM specifically is disrupted in transgenic flies inducibly overexpressing CREB repressor. 1-day memory after massed training, in contrast, is composed only of ARM. Accordingly, these results suggest that ARM is normal and LTM is completely abolished in EP331/+, hs-GAL4/+ flies after acute disruption of dNR1. The observation that 1-day memory after massed training was normal also suggested that extended training might overcome the learning defect (after one training session) observed for EP331/+, hs-GAL4/+ flies subjected to heat shock. Indeed, this was the case for both spaced and massed training (Xia, 2005).
A modified massed training protocol was used, in which flies sat in the training chamber for 150 min before training began. With this protocol, massed training ends at the same time as spaced training, but 1-day memory after massed training is slightly higher than that after the standard protocol, which does not include pretraining exposure to the training chamber. Hence, the above experiments were repeated with the original massed training protocol with only heat-shocked wild-type and EP331/+, hs-GAL4/+ flies. Here again, 1-day memory after massed training was normal, whereas that after spaced training was disrupted (Xia, 2005).
Although dNR1 was expressed throughout the adult brain and especially also at the lateral protocerebrum (LP), sensorimotor responses to the odors and footshock stimuli were not affected in transheterozygous EP331/+, hs-GAL4/+ flies before or after heat shock. Homozygous EP3511/EP3511 and EP331/EP331 mutants also performed normally to these sensory stimuli (Xia, 2005).
Reference names in red indicate recommended papers.
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date revised: 1 August 2008
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