• Pf4-Grin1−/− mice have prolonged bleeding time and impaired PPF.

  • NMDAR regulates cytoskeletal reorganization in platelets and MKs upon cell contact with matrix.

The process of proplatelet formation (PPF) requires coordinated interaction between megakaryocytes (MKs) and the extracellular matrix (ECM), followed by a dynamic reorganization of the actin and microtubule cytoskeleton. Localized fluxes of intracellular calcium ions (Ca2+) facilitate MK-ECM interaction and PPF. Glutamate-gated N-methyl-D-aspartate receptor (NMDAR) is highly permeable to Ca2+. NMDAR antagonists inhibit MK maturation ex vivo; however, there are no in vivo data. Using the Cre-loxP system, we generated a platelet lineage–specific knockout mouse model of reduced NMDAR function in MKs and platelets (Pf4-Grin1−/− mice). Effects of NMDAR deletion were examined using well-established assays of platelet function and production in vivo and ex vivo. We found that Pf4-Grin1−/− mice had defects in megakaryopoiesis, thrombopoiesis, and platelet function, which manifested as reduced platelet counts, lower rates of platelet production in the immune model of thrombocytopenia, and prolonged tail bleeding time. Platelet activation was impaired to a range of agonists associated with reduced Ca2+ responses, including metabotropic like, and defective platelet spreading. MKs showed reduced colony and proplatelet formation. Impaired reorganization of intracellular F-actin and α-tubulin was identified as the main cause of reduced platelet function and production. Pf4-Grin1−/− MKs also had lower levels of transcripts encoding crucial ECM elements and enzymes, suggesting NMDAR signaling is involved in ECM remodeling. In summary, we provide the first genetic evidence that NMDAR plays an active role in platelet function and production. NMDAR regulates PPF through a mechanism that involves MK-ECM interaction and cytoskeletal reorganization. Our results suggest that NMDAR helps guide PPF in vivo.

1.
Eckly
A
,
Scandola
C
,
Oprescu
A
, et al
.
Megakaryocytes use in vivo podosome-like structures working collectively to penetrate the endothelial barrier of bone marrow sinusoids
.
J Thromb Haemost.
2020
;
18
(
11
):
2987
-
3001
.
2.
Abbonante
V
,
Di Buduo
CA
,
Malara
A
,
Laurent
PA
,
Balduini
A
.
Mechanisms of platelet release: in vivo studies and in vitro modeling
.
Platelets.
2020
;
31
(
6
):
717
-
723
.
3.
Machlus
KR
,
Italiano
JE
Jr
.
The incredible journey: from megakaryocyte development to platelet formation
.
J Cell Biol.
2013
;
201
(
6
):
785
-
796
.
4.
Thon
JN
,
Montalvo
A
,
Patel-Hett
S
, et al
.
Cytoskeletal mechanics of proplatelet maturation and platelet release
.
J Cell Biol.
2010
;
191
(
4
):
861
-
874
.
5.
Ghalloussi
D
,
Dhenge
A
,
Bergmeier
W
.
New insights into cytoskeletal remodeling during platelet production
.
J Thromb Haemost.
2019
;
17
(
9
):
1430
-
1439
.
6.
Mbiandjeu
S
,
Balduini
A
,
Malara
A
.
Megakaryocyte cytoskeletal proteins in platelet biogenesis and diseases [published online ahead of print 4 July 2021]
.
Thromb Haemost
.
7.
Kaushansky
K
,
Lok
S
,
Holly
RD
, et al
.
Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin
.
Nature.
1994
;
369
(
6481
):
568
-
571
.
8.
Ng
AP
,
Kauppi
M
,
Metcalf
D
, et al
.
Mpl expression on megakaryocytes and platelets is dispensable for thrombopoiesis but essential to prevent myeloproliferation
.
Proc Natl Acad Sci USA.
2014
;
111
(
16
):
5884
-
5889
.
9.
Zhang
L
,
Orban
M
,
Lorenz
M
, et al
.
A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis
.
J Exp Med.
2012
;
209
(
12
):
2165
-
2181
.
10.
Niazi
H
,
Zoghdani
N
,
Couty
L
, et al
.
Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing
.
Blood Adv.
2019
;
3
(
11
):
1702
-
1713
.
11.
Stegner
D
,
Nieswandt
B
.
Platelet receptor signaling in thrombus formation
.
J Mol Med (Berl).
2011
;
89
(
2
):
109
-
121
.
12.
Abbasian
N
,
Millington-Burgess
SL
,
Chabra
S
,
Malcor
JD
,
Harper
MT
.
Supramaximal calcium signaling triggers procoagulant platelet formation
.
Blood Adv.
2020
;
4
(
1
):
154
-
164
.
13.
Ngo
ATP
,
Jongen
M
,
Shatzel
JJ
,
McCarty
OJT
.
Platelet integrin activation surfs the calcium waves
.
Platelets.
2021
;
32
(
4
):
437
-
439
.
14.
Di Buduo
CA
,
Balduini
A
,
Moccia
F
.
Pathophysiological significance of store-operated calcium entry in megakaryocyte function: opening new paths for understanding the role of calcium in thrombopoiesis
.
Int J Mol Sci.
2016
;
17
(
12
):
2055
.
15.
Braun
A
,
Varga-Szabo
D
,
Kleinschnitz
C
, et al
.
Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation
.
Blood.
2009
;
113
(
9
):
2056
-
2063
.
16.
Di Buduo
CA
,
Moccia
F
,
Battiston
M
, et al
.
The importance of calcium in the regulation of megakaryocyte function
.
Haematologica.
2014
;
99
(
4
):
769
-
778
.
17.
Ilkan
Z
,
Wright
JR
,
Goodall
AH
,
Gibbins
JM
,
Jones
CI
,
Mahaut-Smith
MP
.
Evidence for shear-mediated Ca2+ entry through mechanosensitive cation channels in human platelets and a megakaryocytic cell line
.
J Biol Chem.
2017
;
292
(
22
):
9204
-
9217
.
18.
Abbonante
V
,
Di Buduo
CA
,
Gruppi
C
, et al
.
A new path to platelet production through matrix sensing
.
Haematologica.
2017
;
102
(
7
):
1150
-
1160
.
19.
Mountford
JC
,
Melford
SK
,
Bunce
CM
,
Gibbins
J
,
Watson
SP
.
Collagen or collagen-related peptide cause (Ca2+)i elevation and increased tyrosine phosphorylation in human megakaryocytes
.
Thromb Haemost.
1999
;
82
(
3
):
1153
-
1159
.
20.
Hansen
KB
,
Yi
F
,
Perszyk
RE
, et al
.
Structure, function, and allosteric modulation of NMDA receptors
.
J Gen Physiol.
2018
;
150
(
8
):
1081
-
1105
.
21.
Hogan-Cann
AD
,
Anderson
CM
.
Physiological roles of non-neuronal NMDA receptors
.
Trends Pharmacol Sci.
2016
;
37
(
9
):
750
-
767
.
22.
Negri
S
,
Faris
P
,
Maniezzi
C
, et al
.
NMDA receptors elicit flux-independent intracellular Ca(2+) signals via metabotropic glutamate receptors and flux-dependent nitric oxide release in human brain microvascular endothelial cells
.
Cell Calcium.
2021
;
99
:
102454
.
23.
Dong
YN
,
Hsu
FC
,
Koziol-White
CJ
, et al
.
Functional NMDA receptors are expressed by human pulmonary artery smooth muscle cells
.
Sci Rep.
2021
;
11
(
1
):
8205
.
24.
Kalev-Zylinska
ML
,
Green
TN
,
Morel-Kopp
MC
, et al
.
N-methyl-D-aspartate receptors amplify activation and aggregation of human platelets
.
Thromb Res.
2014
;
133
(
5
):
837
-
847
.
25.
Green
TN
,
Hamilton
JR
,
Morel-Kopp
MC
, et al
.
Inhibition of NMDA receptor function with an anti-GluN1-S2 antibody impairs human platelet function and thrombosis
.
Platelets.
2017
;
28
(
8
):
799
-
811
.
26.
Chatterjee
M
,
Ehrenberg
A
,
Toska
LM
, et al
.
Molecular drivers of platelet activation: unraveling novel targets for anti-thrombotic and anti-thrombo-inflammatory therapy
.
Int J Mol Sci.
2020
;
21
(
21
):
7906
.
27.
Hitchcock
IS
,
Skerry
TM
,
Howard
MR
,
Genever
PG
.
NMDA receptor-mediated regulation of human megakaryocytopoiesis
.
Blood.
2003
;
102
(
4
):
1254
-
1259
.
28.
Kamal
T
,
Green
TN
,
Hearn
JI
, et al
.
N-methyl-d-aspartate receptor mediated calcium influx supports in vitro differentiation of normal mouse megakaryocytes but proliferation of leukemic cell lines
.
Res Pract Thromb Haemost.
2017
;
2
(
1
):
125
-
138
.
29.
Genever
PG
,
Wilkinson
DJ
,
Patton
AJ
, et al
.
Expression of a functional N-methyl-D-aspartate-type glutamate receptor by bone marrow megakaryocytes
.
Blood.
1999
;
93
(
9
):
2876
-
2883
.
30.
Tiedt
R
,
Schomber
T
,
Hao-Shen
H
,
Skoda
RC
.
Pf4-Cre transgenic mice allow the generation of lineage-restricted gene knockouts for studying megakaryocyte and platelet function in vivo
.
Blood.
2007
;
109
(
4
):
1503
-
1506
.
31.
Tsien
JZ
,
Huerta
PT
,
Tonegawa
S
.
The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory
.
Cell.
1996
;
87
(
7
):
1327
-
1338
.
32.
Ohlmann
P
,
Hechler
B
,
Cazenave
JP
,
Gachet
C
.
Measurement and manipulation of [Ca2+]i in suspensions of platelets and cell cultures
.
Methods Mol Biol.
2004
;
273
:
229
-
250
.
33.
Zaykin
DV
.
Optimally weighted Z-test is a powerful method for combining probabilities in meta-analysis
.
J Evol Biol.
2011
;
24
(
8
):
1836
-
1841
.
34.
Becker
BJ
. Combining significance levels. In:
Cooper
H
,
Hedges
LV
, eds.
The Handbook of Research Synthesis.
New York, NY
:
Russell Sage Foundation
;
1994
:
215
-
230
.
35.
Forrest
D
,
Yuzaki
M
,
Soares
HD
, et al
.
Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death
.
Neuron.
1994
;
13
(
2
):
325
-
338
.
36.
Makhro
A
,
Wang
J
,
Vogel
J
, et al
.
Functional NMDA receptors in rat erythrocytes
.
Am J Physiol Cell Physiol.
2010
;
298
(
6
):
C1315
-
C1325
.
37.
Fenninger
F
,
Jefferies
WA
.
What’s bred in the bone: calcium channels in lymphocytes
.
J Immunol.
2019
;
202
(
4
):
1021
-
1030
.
38.
Del Arroyo
AG
,
Hadjihambi
A
,
Sanchez
J
, et al
.
NMDA receptor modulation of glutamate release in activated neutrophils
.
EBioMedicine.
2019
;
47
:
457
-
469
.
39.
Makhro
A
,
Hänggi
P
,
Goede
JS
, et al
.
N-methyl-D-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation
.
Am J Physiol Cell Physiol.
2013
;
305
(
11
):
C1123
-
C1138
.
40.
Morrell
CN
,
Sun
H
,
Ikeda
M
, et al
.
Glutamate mediates platelet activation through the AMPA receptor
.
J Exp Med.
2008
;
205
(
3
):
575
-
584
.
41.
Montes de Oca Balderas
P
,
Aguilera
P
.
A metabotropic-like flux-independent NMDA receptor regulates Ca2+ exit from endoplasmic reticulum and mitochondrial membrane potential in cultured astrocytes [published correction appears in PLoS One. 2018;13(8):e0202819]
.
PLoS One.
2015
;
10
(
5
):
e0126314
.
42.
Montes de Oca Balderas
P
.
Flux-independent NMDAR signaling: molecular mediators, cellular functions, and complexities
.
Int J Mol Sci.
2018
;
19
(
12
):
3800
.
43.
Varga-Szabo
D
,
Braun
A
,
Nieswandt
B
.
Calcium signaling in platelets
.
J Thromb Haemost.
2009
;
7
(
7
):
1057
-
1066
.
44.
Gruszczynska-Biegala
J
,
Strucinska
K
,
Maciag
F
,
Majewski
L
,
Sladowska
M
,
Kuznicki
J
.
STIM protein-NMDA2 receptor interaction decreases NMDA-dependent calcium levels in cortical neurons
.
Cells.
2020
;
9
(
1
):
160
.
45.
Kiessling
K
,
Roberts
N
,
Gibson
JS
,
Ellory
JC
.
A comparison in normal individuals and sickle cell patients of reduced glutathione precursors and their transport between plasma and red cells
.
Hematol J.
2000
;
1
(
4
):
243
-
249
.
46.
Nishimura
S
,
Nagasaki
M
,
Kunishima
S
, et al
.
IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs
.
J Cell Biol.
2015
;
209
(
3
):
453
-
466
.
47.
Kowata
S
,
Isogai
S
,
Murai
K
, et al
.
Platelet demand modulates the type of intravascular protrusion of megakaryocytes in bone marrow
.
Thromb Haemost.
2014
;
112
(
4
):
743
-
756
.
48.
Aguilar
A
,
Pertuy
F
,
Eckly
A
, et al
.
Importance of environmental stiffness for megakaryocyte differentiation and proplatelet formation
.
Blood.
2016
;
128
(
16
):
2022
-
2032
.
49.
Berridge
MJ
,
Bootman
MD
,
Roderick
HL
.
Calcium signalling: dynamics, homeostasis and remodelling
.
Nat Rev Mol Cell Biol.
2003
;
4
(
7
):
517
-
529
.
50.
Birnbaumer
L
.
The TRPC class of ion channels: a critical review of their roles in slow, sustained increases in intracellular Ca(2+) concentrations
.
Annu Rev Pharmacol Toxicol.
2009
;
49
:
395
-
426
.
51.
Wright
JR
,
Amisten
S
,
Goodall
AH
,
Mahaut-Smith
MP
.
Transcriptomic analysis of the ion channelome of human platelets and megakaryocytic cell lines
.
Thromb Haemost.
2016
;
116
(
2
):
272
-
284
.
52.
Carter
RN
,
Tolhurst
G
,
Walmsley
G
,
Vizuete-Forster
M
,
Miller
N
,
Mahaut-Smith
MP
.
Molecular and electrophysiological characterization of transient receptor potential ion channels in the primary murine megakaryocyte
.
J Physiol.
2006
;
576
(
Pt 1
):
151
-
162
.
53.
Furuyashiki
T
,
Arakawa
Y
,
Takemoto-Kimura
S
,
Bito
H
,
Narumiya
S
.
Multiple spatiotemporal modes of actin reorganization by NMDA receptors and voltage-gated Ca2+ channels
.
Proc Natl Acad Sci USA.
2002
;
99
(
22
):
14458
-
14463
.
54.
Malara
A
,
Currao
M
,
Gruppi
C
, et al
.
Megakaryocytes contribute to the bone marrow-matrix environment by expressing fibronectin, type IV collagen, and laminin
.
Stem Cells.
2014
;
32
(
4
):
926
-
937
.
55.
Gautam
D
,
Tiwari
A
,
Nath Chaurasia
R
,
Dash
D
.
Glutamate induces synthesis of thrombogenic peptides and extracellular vesicle release from human platelets
.
Sci Rep.
2019
;
9
(
1
):
8346
.
56.
Balduini
A
,
Di Buduo
CA
,
Malara
A
, et al
.
Constitutively released adenosine diphosphate regulates proplatelet formation by human megakaryocytes
.
Haematologica.
2012
;
97
(
11
):
1657
-
1665
.
57.
Woulfe
D
,
Yang
J
,
Brass
L
.
ADP and platelets: the end of the beginning
.
J Clin Invest.
2001
;
107
(
12
):
1503
-
1505
.
58.
Thompson
CJ
,
Schilling
T
,
Howard
MR
,
Genever
PG
.
SNARE-dependent glutamate release in megakaryocytes
.
Exp Hematol.
2010
;
38
(
6
):
504
-
515
.
59.
Gray
L
,
McOmish
CE
,
Scarr
E
,
Dean
B
,
Hannan
AJ
.
Sensitivity to MK-801 in phospholipase C-β1 knockout mice reveals a specific NMDA receptor deficit
.
Int J Neuropsychopharmacol.
2009
;
12
(
7
):
917
-
928
.
60.
Horne
EA
,
Dell’Acqua
ML
.
Phospholipase C is required for changes in postsynaptic structure and function associated with NMDA receptor-dependent long-term depression
.
J Neurosci.
2007
;
27
(
13
):
3523
-
3534
.
61.
Frere
SG
,
Chang-Ileto
B
,
Di Paolo
G
.
Role of phosphoinositides at the neuronal synapse
.
Subcell Biochem.
2012
;
59
:
131
-
175
.
62.
Balduini
A
,
Fava
C
,
Di Buduo
CA
, et al
.
Expression and functional characterization of the large-conductance calcium and voltage-activated potassium channel Kca 1.1 in megakaryocytes and platelets
.
J Thromb Haemost.
2021
;
19
(
6
):
1558
-
1571
.
63.
Nilsson
SK
,
Debatis
ME
,
Dooner
MS
,
Madri
JA
,
Quesenberry
PJ
,
Becker
PS
.
Immunofluorescence characterization of key extracellular matrix proteins in murine bone marrow in situ
.
J Histochem Cytochem.
1998
;
46
(
3
):
371
-
377
.
64.
Coutu
DL
,
Kokkaliaris
KD
,
Kunz
L
,
Schroeder
T
.
Three-dimensional map of nonhematopoietic bone and bone-marrow cells and molecules
.
Nat Biotechnol.
2017
;
35
(
12
):
1202
-
1210
.
65.
Semeniak
D
,
Kulawig
R
,
Stegner
D
, et al
.
Proplatelet formation is selectively inhibited by collagen type I through Syk-independent GPVI signaling
.
J Cell Sci.
2016
;
129
(
18
):
3473
-
3484
.
66.
Balduini
A
,
Pallotta
I
,
Malara
A
, et al
.
Adhesive receptors, extracellular proteins and myosin IIA orchestrate proplatelet formation by human megakaryocytes
.
J Thromb Haemost.
2008
;
6
(
11
):
1900
-
1907
.
67.
Malara
A
,
Gruppi
C
,
Pallotta
I
, et al
.
Extracellular matrix structure and nano-mechanics determine megakaryocyte function
.
Blood.
2011
;
118
(
16
):
4449
-
4453
.
68.
Shin
JW
,
Swift
J
,
Spinler
KR
,
Discher
DE
.
Myosin-II inhibition and soft 2D matrix maximize multinucleation and cellular projections typical of platelet-producing megakaryocytes
.
Proc Natl Acad Sci USA.
2011
;
108
(
28
):
11458
-
11463
.
69.
Eliades
A
,
Papadantonakis
N
,
Bhupatiraju
A
, et al
.
Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase
.
J Biol Chem.
2011
;
286
(
31
):
27630
-
27638
.
70.
Malara
A
,
Ligi
D
,
Di Buduo
CA
,
Mannello
F
,
Balduini
A
.
Sub-cellular localization of metalloproteinases in megakaryocytes
.
Cells.
2018
;
7
(
7
):
80
.
71.
Michalick
L
,
Kuebler
WM
.
TRPV4-A missing link between mechanosensation and immunity
.
Front Immunol.
2020
;
11
:
413
.
72.
Harper
AG
,
Brownlow
SL
,
Sage
SO
.
A role for TRPV1 in agonist-evoked activation of human platelets
.
J Thromb Haemost.
2009
;
7
(
2
):
330
-
338
.
73.
Cunin
P
,
Nigrovic
PA
.
Megakaryocytes as immune cells
.
J Leukoc Biol.
2019
;
105
(
6
):
1111
-
1121
.
74.
Pariser
DN
,
Hilt
ZT
,
Ture
SK
, et al
.
Lung megakaryocytes are immune modulatory cells
.
J Clin Invest.
2021
;
131
(
1
):
e137377
.
75.
Rahaman
SO
,
Grove
LM
,
Paruchuri
S
, et al
.
TRPV4 mediates myofibroblast differentiation and pulmonary fibrosis in mice
.
J Clin Invest.
2014
;
124
(
12
):
5225
-
5238
.
76.
Kalev-Zylinska
ML
,
Hearn
JI
,
Rong
J
, et al
.
Altered N-methyl D-aspartate receptor subunit expression causes changes to the circadian clock and cell phenotype in osteoarthritic chondrocytes
.
Osteoarthritis Cartilage.
2018
;
26
(
11
):
1518
-
1530
.
77.
Kundu
S
,
Pushpakumar
S
,
Sen
U
.
MMP-9- and NMDA receptor-mediated mechanism of diabetic renovascular remodeling and kidney dysfunction: hydrogen sulfide is a key modulator
.
Nitric Oxide.
2015
;
46
:
172
-
185
.
78.
Zhou
J
,
Liu
S
,
Guo
L
,
Wang
R
,
Chen
J
,
Shen
J
.
NMDA receptor-mediated CaMKII/ERK activation contributes to renal fibrosis
.
BMC Nephrol.
2020
;
21
(
1
):
392
.
79.
Abbonante
V
,
Chitalia
V
,
Rosti
V
, et al
.
Upregulation of lysyl oxidase and adhesion to collagen of human megakaryocytes and platelets in primary myelofibrosis
.
Blood.
2017
;
130
(
6
):
829
-
831
.
80.
Pietra
D
,
Rumi
E
,
Ferretti
VV
, et al
.
Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms
.
Leukemia.
2016
;
30
(
2
):
431
-
438
.
81.
Di Buduo
CA
,
Abbonante
V
,
Marty
C
, et al
.
Defective interaction of mutant calreticulin and SOCE in megakaryocytes from patients with myeloproliferative neoplasms
.
Blood.
2020
;
135
(
2
):
133
-
144
.
82.
Lagrue-Lak-Hal
AH
,
Debili
N
,
Kingbury
G
, et al
.
Expression and function of the collagen receptor GPVI during megakaryocyte maturation
.
J Biol Chem.
2001
;
276
(
18
):
15316
-
15325
.
83.
Sabri
S
,
Jandrot-Perrus
M
,
Bertoglio
J
, et al
.
Differential regulation of actin stress fiber assembly and proplatelet formation by alpha2beta1 integrin and GPVI in human megakaryocytes
.
Blood.
2004
;
104
(
10
):
3117
-
3125
.
84.
Semeniak
D
,
Faber
K
,
Öftering
P
,
Manukjan
G
,
Schulze
H
.
Impact of Itga2-Gp6-double collagen receptor deficient mice for bone marrow megakaryocytes and platelets
.
PLoS One.
2019
;
14
(
8
):
e0216839
.
85.
Paoletti
P
,
Ascher
P
.
Mechanosensitivity of NMDA receptors in cultured mouse central neurons
.
Neuron.
1994
;
13
(
3
):
645
-
655
.
86.
Lin
B
,
Arai
AC
,
Lynch
G
,
Gall
CM
.
Integrins regulate NMDA receptor-mediated synaptic currents
.
J Neurophysiol.
2003
;
89
(
5
):
2874
-
2878
.
87.
Koser
DE
,
Thompson
AJ
,
Foster
SK
, et al
.
Mechanosensing is critical for axon growth in the developing brain
.
Nat Neurosci.
2016
;
19
(
12
):
1592
-
1598
.
88.
Mathur
BN
,
Deutch
AY
.
Rat meningeal and brain microvasculature pericytes co-express the vesicular glutamate transporters 2 and 3
.
Neurosci Lett.
2008
;
435
(
2
):
90
-
94
.
89.
Rainesalo
S
,
Keränen
T
,
Saransaari
P
,
Honkaniemi
J
.
GABA and glutamate transporters are expressed in human platelets
.
Brain Res Mol Brain Res.
2005
;
141
(
2
):
161
-
165
.
90.
Ahmed
H
,
Haider
A
,
Ametamey
SM
.
N-methyl-D-aspartate (NMDA) receptor modulators: a patent review (2015-present)
.
Expert Opin Ther Pat.
2020
;
30
(
10
):
743
-
767
.
You do not currently have access to this content.

Sign in via your Institution

Sign In