Differentially expressed Drl and Drl-2 play opposing roles in Wnt5 signaling during Drosophila olfactory system development.

In Drosophila, odor information received by olfactory receptor neurons (ORNs) is processed by glomeruli, which are organized in a stereotypic manner in the antennal lobe (AL). This glomerular organization is regulated by Wnt5 signaling. In the embryonic CNS, Wnt5 signaling is transduced by the Drl receptor, a member of the Ryk family. During development of the olfactory system, however, it is antagonized by Drl. Here, we identify Drl-2 as a receptor mediating Wnt5 signaling. Drl is found in the neurites of brain cells in the AL and specific glia, whereas Drl-2 is predominantly found in subsets of growing ORN axons. A drl-2 mutation produces only mild deficits in glomerular patterning, but when it is combined with a drl mutation, the phenotype is exacerbated and more closely resembles the Wnt5 phenotype. Wnt5 overexpression in ORNs induces aberrant glomeruli positioning. This phenotype is ameliorated in the drl-2 mutant background, indicating that Drl-2 mediates Wnt5 signaling. In contrast, forced expression of Drl-2 in the glia of drl mutants rescues the glomerular phenotype caused by the loss of antagonistic Drl function. Therefore, Drl-2 can also antagonize Wnt5 signaling. Additionally, our genetic data suggest that Drl localized to developing glomeruli mediates Wnt5 signaling. Thus, these two members of the Ryk family are capable of carrying out a similar molecular function, but they can play opposing roles in Wnt5 signaling, depending on the type of cells in which they are expressed. These molecules work cooperatively to establish the olfactory circuitry in Drosophila.

A paired-pulse facilitation analysis of long-term synaptic depression at excitatory synapses in rat hippocampal CA1 and CA3 regions.

Paired-pulse facilitation (PPF) is a form of short-term, activity-dependent synaptic plasticity common to most chemically transmitting synapses, manifested as an enhancement in the amplitude of the second of two rapidly evoked excitatory postsynaptic potentials (EPSPs). The generally accepted explanation of PPF posits that residual intraterminal free [Ca(2+)] from the first action potential facilitates the probability of transmitter release evoked by the second stimulus. A common extension of this hypothesis postulates that any plastic change which alters the probability of transmitter release, should also alter the magnitude of PPF. In the present study, we examined the relationship between PPF and both stimulus- and chemically-evoked long-term depression of synaptic strength (LTD) at Schaffer collateral-CA1, commissural/associational-CA3 and mossy fiber-CA3 synapses in rat hippocampal slices. We observed no significant change in mean PPF associated with either electrically- or chemically-induced LTD at any of these synapses. However, a correlation analysis revealed a complex pattern of PPF changes with LTD, such that low initial PPF was correlated with increases in PPF, while high initial PPF was associated with decreases. Combined with previous findings supporting a presynaptic site for chemical and stimulus-evoked LTD, our current data suggests a complex set of neurosecretory modifications downstream of presynaptic Ca(2+) influx, may, at least in part, underlie the expression of LTD.

Activation of receptors negatively coupled to adenylate cyclase is required for induction of long-term synaptic depression at Schaffer collateral-CA1 synapses.

Chemical LTD (CLTD) of synaptic transmission is triggered by simultaneously increasing presynaptic [cGMP] while inhibiting PKA. Here, we supply evidence that class II, but not III, metabotropic glutamate receptors (mGluRs), and A1 adenosine receptors, both negatively coupled to adenylate cyclase, play physiologic roles in providing PKA inhibition necessary to promote the induction of LTD at Schaffer collateral-CA1 synapses in hippocampal slices. Simultaneous activation of group II mGluRs with the selective agonist (2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl) glycine (DCGIV; 5 microM), while raising [cGMP] with the type V phosphodiesterase inhibitor, zaprinast (20 microM), resulted in a long-lasting depression of synaptic strength. When zaprinast (20 microM) was combined with a cell-permeant PKA inhibitor H-89 (10 microM), the need for mGluR IIs was bypassed. DCGIV, when combined with a "submaximal" low frequency stimulation (1 Hz/400 s), produced a saturating LTD. The mGluR II selective antagonist, (2S)-alpha-ethylglutamic acid (EGLU; 5 microM), blocked induction of LTD by prolonged low frequency stimulation (1 Hz/900 s). In contrast, the mGluR III selective receptor blocker, (RS)-a-Cyclopropyl-[3- 3H]-4-phosphonophenylglycine (CPPG; 10 microM), did not impair LTD. The selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 100 nM), also blocked induction of LTD, while the adenosine A1 receptor agonist N6-cyclohexyl adenosine (CHA; 50 nM) significantly enhanced the magnitude of LTD induced by submaximal LFS and, when paired with zaprinast (20 microM), was sufficient to elicit CLTD. Inhibition of PKA with H-89 rescued the expression of LTD in the presence of either EGLU or DPCPX, confirming the hypothesis that both group II mGluRs and A1 adenosine receptors enhance the induction of LTD by inhibiting adenylate cyclase and reducing PKA activity.