Circuit Analysis of a Drosophila Dopamine Type 2 Receptor That Supports Anesthesia-Resistant Memory

Abstract

Dopamine is central to reinforcement processing and exerts this function in species ranging from humans to fruit flies. It can do so via two different types of receptors (i.e., D1 or D2) that mediate either augmentation or abatement of cellular cAMP levels. Whereas D1 receptors are known to contribute to Drosophila aversive odor learning per se, we here show that D2 receptors are specific for support of a consolidated form of odor memory known as anesthesia-resistant memory. By means of genetic mosaicism, we localize this function to Kenyon cells, the mushroom body intrinsic neurons, as well as GABAergic APL neurons and local interneurons of the antennal lobes, suggesting that consolidated anesthesia-resistant memory requires widespread dopaminergic modulation within the olfactory circuit. Additionally, dopaminergic neurons themselves require D2R, suggesting a critical role in dopamine release via its recognized autoreceptor function. Considering the dual role of dopamine in balancing memory acquisition (proactive function of dopamine) and its "forgetting" (retroactive function of dopamine), our analysis suggests D2R as central player of either process.

Drk-mediated signaling to Rho kinase is required for anesthesia-resistant memory in Drosophila

“…36). In addition, the reported role of dopamine and serotonin in ARM (8,10,11) is consistent with the proposed structural plasticity model, as both neurotransmitters have been implicated in spine dynamics in both insects (37) and vertebrates (38,39).…”

“…1B, open bars), indicating that Drk reduction may selectively affect this form of aversive olfactory memory. This was better illustrated after fragmentation of 3-h memory to its components by subtracting the performance after cold shock of controls and mutants from the respective scores of untreated animals (7,11). This verified that 3-h memory comprised nearly equal parts of ASM and ARM for controls (2), and whereas ASM seemed largely unaffected, ARM was severely attenuated for drk ΔP24 /+ (Fig.…”

“…Proteins with demonstrated roles in ARM formation include Radish (Rsh) (5); the constitutively active atypical PKC, PKM (6); the calcium channel Bruchpilot (Brp) (7); the d5HT1A serotonin and Oct2β2 octopamine receptors (8,9); the Dop1R1, Dop2R dopamine receptors (10,11); and Protein Kinase A (12). However, whether these molecules operate in one or more ARMmediating signaling cascades is presently unclear.…”

“…ARM formation appears to require octopaminergic input to the MB α′ß′ lobes from the Anterior Paired Lateral (APL) neurons (9, 16), whereas retrieval requires serotonergic input to the αβ lobes from the Dorsal Paired Medial (DPM) neurons. It appears then that at least two circuits and parallel molecular pathways contribute to ARM (16): an Oct2β2 receptor-mediated Rsh-independent in the α′ß′ lobes (9) and an Rsh-dependent, d5HT1A serotonin receptor-mediated in the αβ (8), which also receives Dop2R-mediated signals (11). Finally, Dop1R1 and Dop2R activities in the γ lobes have been suggested to contribute to ARM (10,11).…”

“…It appears then that at least two circuits and parallel molecular pathways contribute to ARM (16): an Oct2β2 receptor-mediated Rsh-independent in the α′ß′ lobes (9) and an Rsh-dependent, d5HT1A serotonin receptor-mediated in the αβ (8), which also receives Dop2R-mediated signals (11). Finally, Dop1R1 and Dop2R activities in the γ lobes have been suggested to contribute to ARM (10,11). Drk, an SH2-SH3 domain adaptor protein orthologous to the mammalian Grb2, is also expressed preferentially in α/β neurons.…”