Drosophila Neprilysins Are Involved in Middle-Term and Long-Term Memory

doi:10.1523/JNEUROSCI.3730-15.2016

. 2016 Sep 14;36(37):9535-46.

doi: 10.1523/JNEUROSCI.3730-15.2016.

Drosophila Neprilysins Are Involved in Middle-Term and Long-Term Memory

Oriane Turrel¹, Aurélie Lampin-Saint-Amaux¹, Thomas Préat¹, Valérie Goguel²

Affiliations

¹ Genes and Dynamics of Memory Systems, Brain Plasticity Unit, Centre National de la Recherche Scientifique, ESPCI-ParisTech, PSL Research University, 75005 Paris, France.
² Genes and Dynamics of Memory Systems, Brain Plasticity Unit, Centre National de la Recherche Scientifique, ESPCI-ParisTech, PSL Research University, 75005 Paris, France valerie.goguel@espci.fr.

PMID: 27629706
PMCID: PMC6601947
DOI: 10.1523/JNEUROSCI.3730-15.2016

Drosophila Neprilysins Are Involved in Middle-Term and Long-Term Memory

Oriane Turrel et al. J Neurosci. 2016.

. 2016 Sep 14;36(37):9535-46.

doi: 10.1523/JNEUROSCI.3730-15.2016.

Authors

Oriane Turrel¹, Aurélie Lampin-Saint-Amaux¹, Thomas Préat¹, Valérie Goguel²

Affiliations

¹ Genes and Dynamics of Memory Systems, Brain Plasticity Unit, Centre National de la Recherche Scientifique, ESPCI-ParisTech, PSL Research University, 75005 Paris, France.
² Genes and Dynamics of Memory Systems, Brain Plasticity Unit, Centre National de la Recherche Scientifique, ESPCI-ParisTech, PSL Research University, 75005 Paris, France valerie.goguel@espci.fr.

PMID: 27629706
PMCID: PMC6601947
DOI: 10.1523/JNEUROSCI.3730-15.2016

Abstract

Neprilysins are type II metalloproteinases known to degrade and inactivate a number of small peptides. Neprilysins in particular are the major amyloid-β peptide-degrading enzymes. In mouse models of Alzheimer's disease, neprilysin overexpression improves learning and memory deficits, whereas neprilysin deficiency aggravates the behavioral phenotypes. However, whether these enzymes are involved in memory in nonpathological conditions is an open question. Drosophila melanogaster is a well suited model system with which to address this issue. Several memory phases have been characterized in this organism and the neuronal circuits involved are well described. The fly genome contains five neprilysin-encoding genes, four of which are expressed in the adult. Using conditional RNA interference, we show here that all four neprilysins are involved in middle-term and long-term memory. Strikingly, all four are required in a single pair of neurons, the dorsal paired medial (DPM) neurons that broadly innervate the mushroom bodies (MBs), the center of olfactory memory. Neprilysins are also required in the MB, reflecting the functional relationship between the DPM neurons and the MB, a circuit believed to stabilize memories. Together, our data establish a role for neprilysins in two specific memory phases and further show that DPM neurons play a critical role in the proper targeting of neuropeptides involved in these processes.

Significance statement: Neprilysins are endopeptidases known to degrade a number of small peptides. Neprilysin research has essentially focused on their role in Alzheimer's disease and heart failure. Here, we use Drosophila melanogaster to study whether neprilysins are involved in memory. Drosophila can form several types of olfactory memory and the neuronal structures involved are well described. Four neprilysin genes are expressed in adult Drosophila Using conditional RNA interference, we show that all four are specifically involved in middle-term memory (MTM) and long-term memory (LTM) and that their expression is required in the mushroom bodies and also in a single pair of closely connected neurons. The data show that these two neurons play a critical role in targeting neuropeptides essential for MTM and LTM.

Keywords: Drosophila; dorsal paired medial neurons; long-term memory; mushroom bodies; neprilysin; olfactory conditioning.

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Figures

**Figure 1.**
Nep1 inhibition in the adult α/β MB neurons induces a MTM deficit. A, Neprilysin mRNA is targeted efficiently by RNAi-Nep constructs. Shown are qPCR analyses of neprilysin expression. Total RNA was extracted from *elav*/+ and *elav/RNAi-Nep* fly heads and further reverse transcribed with olig(dT) primers. Resulting cDNA was quantified using tubulin (Tub) expression as a reference. Results are shown as ratios to the reference (Nep1: t test, ***p < 0.0001, n = 4; Nep2: t test, ***p < 0.0001, n = 6; Nep3: t test, ***p = 0.0008, n = 4; Nep4: t test, **p = 0.0094, n = 4). B, C, Nep1 expression in adult α/β MB neurons is involved in MTM. B, After 3 d of induction, *Gal80*^ts;c739/Nep1A and */Nep1B* flies exhibit MTM deficits (F_(4,45) = 20.98, p < 0.0001, n ≥ 8; *post hoc* Newman–Keuls test, *Gal80*^ts;c739/Nep1A vs *Gal80*^ts;c739/+ ***p < 0.001, *Gal80*^ts;c739/Nep1A vs +*/Nep1A* ***p < 0.001, *Gal80*^ts;c739/*Nep1B* vs *Gal80*^ts;c739/+ ***p < 0.001, *Gal80*^ts;c739/*Nep1B* vs +*/Nep1B* ***p < 0.001). C, In the absence of Gal4 induction, *Gal80*^ts;c739/Nep1A and */Nep1B* flies exhibit similar MTM scores to their respective genetic controls (F_(4,64) = 2.039, p = 0.1003, n ≥ 11). D, E, Nep2, Nep3, and Nep4 silencing in adult α/β MB neurons does not alter MTM. D, Single Nep knock-down MTM analyses with the *Gal80*^ts;c739 driver. RNAi-expressing flies show similar MTM scores to the genetic controls (Nep2A: F_(2,26) = 0.5832, p = 0.5658, n = 9; Nep3A: F_(2,26) = 0.06404, p = 0.9381, n = 9; Nep4A: F_(2,25) = 1.233, p = 0.3100, n ≥ 8). E, Analyses of double and triple Nep knock-down with the *Gal80*^ts;c739 driver. RNAi-expressing flies show similar MTM scores to their genetic controls (F_(6,106) = 1.250, p = 0.2874, n ≥ 10). Error bars indicate mean ± SEM. PI, Performance index.

**Figure 2.**
Neprilysin inhibition in the adult MB induces LTM deficits. A, B, Neprilysin silencing in the adult MB does not affect learning. A, *Gal80*^ts;238Y/Nep1A and */Nep1B* flies exhibit similar learning scores to the genetic controls (F_(4,49) = 1.591, p = 0.1932, n = 10). B, Concomitant silencing of Nep2, Nep3, and Nep4 does not affect learning. *Gal80*^ts;238Y/Nep2A;Nep3A;Nep4A flies exhibit similar learning scores to the genetic controls (F_(2,27) = 1.681, p = 0.2066, n ≥ 9). C, D, Neprilysin silencing in the adult MB does not impact ARM. C, *Gal80*^ts;238Y/Nep1A and */Nep1B* flies exhibit similar memory scores to the genetic controls (F_(4,73) = 2.075, p = 0.0934, n ≥ 14). D, Concomitant silencing of Nep2, Nep3, and Nep4 does not affect ARM. *Gal80*^ts;238Y/Nep2A;Nep3A;Nep4A flies exhibit similar ARM scores to the genetic controls (F_(2,41) = 1.929, p = 0.1589, n = 14). E–H, LTM analyses. E, Nep1 expression is required in adult α/β neurons for LTM formation. After induction, *Gal80*^ts;c739/Nep1A and */Nep1B* flies exhibit a strong LTM impairment (F_(4,54) = 14.36, p < 0.0001, n ≥ 9; *post hoc* Newman–Keuls test, *Gal80*^ts;c739/Nep1A vs *Gal80*^ts;c739/+ ***p < 0.001, *Gal80*^ts;c739/Nep1A vs +*/Nep1A* ***p < 0.001, *Gal80*^ts;c739/Nep1B vs *Gal80*^ts;c739/+ ***p < 0.001, *Gal80*^ts;c739/Nep1B vs +*/Nep1B* ***p < 0.001). In contrast, noninduced flies show similar LTM scores to the genetic controls (F_(4,40) = 1.399, p = 0.2539, n ≥ 8). F, Nep2, Nep3, and Nep4 inhibition in adult α/β neurons does not alter LTM (Nep2A: F_(2,29) = 0.06101, p = 0.9409, n = 10; Nep3A: F_(2,50) = 2.183, p = 0.1237, n ≥ 10; Nep4A: F_(2,50) = 1.380, p = 0.2615, n ≥ 11). G, LTM analyses of double and triple Nep knock-down in adult α/β neurons. Nep2 + Nep3, Nep3 + Nep4, and Nep2 + Nep3 + Nep4 knock-down alter LTM (Nep2A;Nep3A: F_(2,43) = 5.785, p = 0.0061, n ≥ 14; *post hoc* Newman–Keuls test, *Gal80*^ts;c739/Nep2A;Nep3A vs *Gal80*^ts;c739/+ **p < 0.01, *Gal80*^ts;c739/Nep2A;Nep3A vs +*/ Nep2A;Nep3A* *p < 0.05; Nep3A;Nep4A: F_(2,44) = 5.876, p = 0.0056, n = 15; *post hoc* Newman–Keuls test, *Gal80*^ts;c739/Nep3A;Nep4A vs *Gal80*^ts;c739/+ **p < 0.01, *Gal80*^ts;c739/Nep3A;Nep4A vs +*/Nep3A;Nep4A* *p < 0.05; Nep2A;Nep3A;Nep4A: F_(2,38) = 3.986, p = 0.0273, n ≥ 12; *post hoc* Newman–Keuls test, *Gal80*^ts;c739/Nep2A;Nep3A;Nep4A vs *Gal80*^ts;c739/+ *p < 0.05, *Gal80*^ts;c739/Nep2A;Nep3A;Nep4A vs +*/Nep2A;Nep3A;Nep4A* *p < 0.05), whereas Nep2 + Nep4 double knock-down does not (F_(2,38) = 0.1079, p = 0.8980, n = 13). H, In the absence of induction, all genotypes exhibit normal LTM scores (F_(2,42) = 0.2195, p = 0.8039, n ≥ 14).

**Figure 3.**
Constitutive inhibition of neprilysin expression in DPM neurons induces MTM deficits. A, Flies expressing RNAi-Nep under the control of the constitutive *MB-Gal80;c316* driver exhibit significantly lower MTM scores than the genetic controls (Nep1A: F_(2,31) = 11.73, p = 0.0002, n ≥ 8, *post hoc* Newman–Keuls test, *MB-Gal80;c316/Nep1A* vs *MB-Gal80;c316*/+ **p < 0.01, *MB-Gal80;c316/Nep1A* vs +*/Nep1A* ***p < 0.001; Nep2A: F_(2,31) = 10.72, p = 0.0003, n ≥ 8, *post hoc* Newman–Keuls test, *MB-Gal80;c316/Nep2A* vs *MB-Gal80;c316*/+ **p < 0.01, *MB-Gal80;c316/Nep2A* vs +*/Nep2A* ***p < 0.001; Nep3A: F_(2,47) = 18.58, p < 0.0001, n = 16, *post hoc* Newman–Keuls test, *MB-Gal80;c316/Nep3A* vs *MB-Gal80;c316*/+ ***p < 0.001, *MB-Gal80;c316/Nep3A* vs +*/Nep3A* ***p < 0.001; Nep4A: F_(2,46) = 6.939, p = 0.0024, n ≥ 15, *post hoc* Newman–Keuls test, *MB-Gal80;c316/Nep4A* vs *MB-Gal80;c316*/+ **p < 0.01, *MB-Gal80;c316/Nep4A* vs +*/Nep4A* **p < 0.01). B, Neprilysin inhibition in DPM neurons impairs MTM. *VT64246/Nep1A*, */Nep2A*, */Nep3A*, and */Nep4A* flies exhibit MTM deficits compared with the genetic controls (Nep1A: F_(2,30) = 7.403, p = 0.0026, n ≥ 9, *post hoc* Newman–Keuls test, *VT64246*/*Nep1A* vs *VT64246*/+ **p < 0.01, *VT64246/Nep1A* vs +*/Nep1A* **p < 0.01; Nep2A: F_(2,29) = 7.942, p = 0.0019, n ≥ 8, *post hoc* Newman–Keuls test, *VT64246/Nep2A* vs *VT64246*/+ **p < 0.01, *VT64246*/*Nep2A* vs +*/Nep2A* **p < 0.01; Nep3A: F_(2,41) = 21.33, p < 0.0001, n = 14, *post hoc* Newman–Keuls test, *VT64246/Nep3A* vs *VT64246*/+ ***p < 0.001, *VT64246/Nep3A* vs +*/Nep3A* ***p < 0.001; Nep4A: F_(2,49) = 3.872, p = 0.0278, n ≥ 16, *post hoc* Newman–Keuls test, *VT64246*/*Nep4A* vs *VT64246*/+ *p < 0.05, *VT64246*/*Nep4A* vs +*/Nep4A* *p < 0.05).

**Figure 4.**
Neprilysin inhibition in adult DPM neurons induces MTM deficits. A, B, MTM analyses of flies expressing RNAi-Nep(A) in adult DPM neurons. A, After 3 d of induction, *Gal80*^ts;*VT64246*/*Nep1A*, */Nep2A*, */Nep3A* and */Nep4A* flies exhibit MTM deficits compared with the genetic controls (Nep1A: F_(2,73) = 4.125, p = 0.0202, n ≥ 23, *post hoc* Newman–Keuls test, *Gal80*^ts;*VT64246*/*Nep1A* vs *Gal80*^ts;*VT64246*/+ *p < 0.05, *Gal80*^ts;VT64246/Nep1A vs +*/Nep1A* *p < 0.05; Nep2A: F_(2,34) = 4.729, p = 0.0159, n ≥ 11, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep2A vs *Gal80*^ts;VT64246/+ *p < 0.05, *Gal80*^ts;VT64246/Nep2A vs +*/Nep2A* *p < 0.05; Nep3A: F_(2,28) = 8.327, p = 0.0016, n ≥ 9, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep3A vs *Gal80*^ts;VT64246/+ **p < 0.01, *Gal80*^ts;VT64246/Nep3A vs +*/Nep3A* **p < 0.01; Nep4A: F_(2,73) = 5.493, p = 0.0061, n ≥ 24, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep4A vs *Gal80*^ts;VT64246/+ **p < 0.01, *Gal80*^ts;VT64246/Nep4A vs +*/Nep4A* *p < 0.05). B, Noninduced flies show similar MTM scores to the genetic controls (Nep1A: F_(2,26) = 1.300, p = 0.2910, n ≥ 8; Nep2A: F_(2,26) = 2.942, p = 0.0720, n ≥ 7; Nep3A: F_(2,35) = 1.323, p = 0.2801, n = 12; Nep4A: F_(2,58) = 0.5983, p = 0.5532, n ≥ 19). C, D, MTM analyses of flies expressing RNAi-Nep(B) in adult DPM neurons. C, After 3 d of induction, *Gal80*^ts;VT64246/Nep1B, */Nep2B*, */Nep3B* and */Nep4B* flies exhibit significantly lower MTM scores than the genetic controls (Nep1B: F_(2,41) = 17.03, p < 0.0001, n = 14, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep1B vs *Gal80*^ts;VT64246/+ ***p < 0.001, *Gal80*^ts;VT64246/Nep1B vs +*/Nep1B* ***p < 0.001; Nep2B: F_(2,39) = 9.124, p = 0.0006, n ≥ 12, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep2B vs *Gal80*^ts;VT64246/+ *p < 0.05, *Gal80*^ts;VT64246/Nep2B vs +*/Nep2B* ***p < 0.001; Nep3B: F_(2,44) = 3.669, p = 0.0340, n ≥ 13, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep3B vs *Gal80*^ts;VT64246/+ *p < 0.05, *Gal80*^ts;VT64246/Nep3B vs +*/Nep3B* *p < 0.05; Nep4B: F_(2,53) = 6.527, p = 0.0030, n ≥ 15, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep4B vs *Gal80*^ts;VT64246/+ *p < 0.05, *Gal80*^ts;VT64246/Nep4B vs +*/Nep4B* **p < 0.01). D, Noninduced flies show normal MTM scores (Nep1B: F_(2,30) = 5.178, p = 0.0122, n ≥ 10, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep1B vs +*/Nep1B* *p < 0.05; Nep2B: F_(2,33) = 3.422, p = 0.0454, n ≥ 10; Nep3B: F_(2,32) = 1.703, p = 0.1993, n = 11; Nep4B: F_(2,33) = 0.1703, p = 0.8442, n ≥ 10).

**Figure 5.**
Nep1, Nep3 and Nep4 are required in adult DPM neurons for LTM. A, B, Neprilysin silencing in adult DPM neurons does not alter learning. A, *Gal80*^ts;VT64246/Nep1A, */Nep2A*, */Nep3A* and /*Nep4A* flies display similar learning scores to controls (Nep1A: F_(2,24) = 1.296, p = 0.2936, n ≥ 7; Nep2A: F_(2,29) = 0.7634, p = 0.4759, n = 10; Nep3A: F_(2,21) = 1.057, p = 0.3671, n ≥ 6; Nep4A: F_(2,26) = 0.3883, p = 0.6824, n = 9). B, Concomitant silencing of Nep2, Nep3, and Nep4 does not affect learning. *Gal80*^ts;VT64246/Nep2A;Nep3A;Nep4A flies exhibit similar learning scores to the genetic controls (F_(2,25) = 0.8933, p = 0.423, n ≥ 8). C, D, Neprilysin silencing in adult DPM neurons does not alter ARM. C, *Gal80*^ts;VT64246/Nep1A, */Nep2A*, */Nep3A*, and /*Nep4A* flies display similar memory scores to controls (Nep1A: F_(2,36) = 2.079, p = 0.1407, n ≥ 12; Nep2A: F_(2,37) = 0.2217, p = 0.8022, n ≥ 10; Nep3A: F_(2,31) = 0.3567, p = 0.7030, n ≥ 10; Nep4A: F_(2,34) = 0.5298, p = 0.5938, n ≥ 11). D, *Gal80*^ts;VT64246/Nep2A;Nep3A;Nep4A flies exhibit normal ARM scores (F_(2,39) = 0.0344, p = 0.9966, n ≥ 13). E–H, Nep1, Nep3, and Nep4 are required in DPM neurons for LTM. E, *Gal80*^ts;VT64246/Nep1A, */Nep3A* and /*Nep4A* flies show LTM deficits (Nep1A: F_(2,37) = 7.369, p = 0.0021, n ≥ 10, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep1A vs *Gal80*^ts;VT64246/+ **p < 0.01, *Gal80*^ts;VT64246/Nep1A vs +*/Nep1A* **p < 0.01; Nep3A: F_(2,45) = 10.49, p = 0.0002, n ≥ 15, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep3A vs *Gal80*^ts;VT64246/+ *p < 0.05, *Gal80*^ts;VT64246/Nep3A vs +*/Nep3A* ***p < 0.001; Nep4A: F_(2,38) = 10.08, p = 0.0003, n = 13, *post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep4A vs *Gal80*^ts;VT64246/+ **p < 0.01, *Gal80*^ts;VT64246/Nep4A vs +*/Nep4A* ***p < 0.001). F, In the absence of induction, *Gal80*^ts;VT64246/Nep1A, */Nep3A* and /*Nep4A* flies display similar LTM scores to the genetic controls (Nep1A: F_(2,67) = 1.316, p = 0.2752, n ≥ 20; Nep3A: F_(2,53) = 0.4687, p = 0.6285, n ≥ 17; Nep4A: F_(2,39) = 0.1010, p = 0.9042, n ≥ 13). G, H, Nep2 silencing in DPM neurons does not impact LTM. G, *Gal80*^ts;VT64246/Nep2A flies exhibit similar LTM scores to controls (Nep2A: F_(2,47) = 0.5551, p = 0.5779, n ≥ 15). H, Memory formed after 5 spaced training cycles by *Gal80*^ts;VT64246/Nep2A-induced flies is LTM. Treatment with CXM (CXM) induces a memory decrease for all genotypes tested [F_(5,88) = 10.87, p < 0.0001, n ≥ 14; *post hoc* Newman–Keuls test, + vs + (CXM) ***p < 0.001, *Gal80*^ts;VT64246/+ vs *Gal80*^ts;VT64246/+ (CXM) *p < 0.05, *Gal80*^ts;VT64246/Nep2A vs *Gal80*^ts;VT64246/Nep2A (CXM) **p < 0.01]. After CXM treatment, the remaining memory of *Gal80*^ts;VT64246/Nep2A flies is similar to that of their genetic control group (*post hoc* Newman–Keuls test, *Gal80*^ts;VT64246/Nep2A (CXM) vs *Gal80*^ts;VT64246/+ (CXM) p > 0.05).

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References

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1. Bland ND, Thomas JE, Audsley N, Shirras AD, Turner AJ, Isaac RE. Expression of NEP2, a soluble neprilysin-like endopeptidase, during embryogenesis in Drosophila melanogaster. Peptides. 2007;28:127–135. doi: 10.1016/j.peptides.2006.08.032. - DOI - PubMed
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[1] Arimura A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn J Physiol. 1998;48:301–331. doi: 10.2170/jjphysiol.48.301. - DOI - PubMed

[2] Arimura A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn J Physiol. 1998;48:301–331. doi: 10.2170/jjphysiol.48.301. - DOI - PubMed

[3] Aso Y, Grübel K, Busch S, Friedrich AB, Siwanowicz I, Tanimoto H. The mushroom body of adult Drosophila characterized by GAL4 drivers. J Neurogenet. 2009;23:156–172. doi: 10.1080/01677060802471718. - DOI - PubMed

[4] Aso Y, Grübel K, Busch S, Friedrich AB, Siwanowicz I, Tanimoto H. The mushroom body of adult Drosophila characterized by GAL4 drivers. J Neurogenet. 2009;23:156–172. doi: 10.1080/01677060802471718. - DOI - PubMed

[5] Barnstedt O, Owald D, Felsenberg J, Brain R, Moszynski JP, Talbot CB, Perrat PN, Waddell S. Memory-relevant mushroom body output synapses are cholinergic. Neuron. 2016;89:1237–1247. doi: 10.1016/j.neuron.2016.02.015. - DOI - PMC - PubMed

[6] Barnstedt O, Owald D, Felsenberg J, Brain R, Moszynski JP, Talbot CB, Perrat PN, Waddell S. Memory-relevant mushroom body output synapses are cholinergic. Neuron. 2016;89:1237–1247. doi: 10.1016/j.neuron.2016.02.015. - DOI - PMC - PubMed

[7] Bland ND, Thomas JE, Audsley N, Shirras AD, Turner AJ, Isaac RE. Expression of NEP2, a soluble neprilysin-like endopeptidase, during embryogenesis in Drosophila melanogaster. Peptides. 2007;28:127–135. doi: 10.1016/j.peptides.2006.08.032. - DOI - PubMed

[8] Bland ND, Thomas JE, Audsley N, Shirras AD, Turner AJ, Isaac RE. Expression of NEP2, a soluble neprilysin-like endopeptidase, during embryogenesis in Drosophila melanogaster. Peptides. 2007;28:127–135. doi: 10.1016/j.peptides.2006.08.032. - DOI - PubMed

[9] Bland ND, Pinney JW, Thomas JE, Turner AJ, Isaac RE. Bioinformatic analysis of the neprilysin (M13) family of peptidases reveals complex evolutionary and functional relationships. BMC Evol Biol. 2008:8. - PMC - PubMed

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Drosophila Neprilysins Are Involved in Middle-Term and Long-Term Memory

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Drosophila Neprilysins Are Involved in Middle-Term and Long-Term Memory

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