ORIGINAL RESEARCH

published: 30 September 2021

doi: 10.3389/fpsyt.2021.671151

L-Carnitine and Acetyl-L-Carnitine:

Potential Novel Biomarkers for Major
Depressive Disorder
Li-Juan Nie 1,2,3,4 , Jun Liang 1,2,3,4 , Feng Shan 1,2,3,4 , Bao-Shi Wang 1,2,3,4 , Yuan-Yuan Mu 1,2,3,4 ,
Xie-Hai Zhou 1,2,3,4 and Qing-Rong Xia 1,2,3,4*
1
Affiliated Psychological Hospital of Anhui Medical University, Hefei, China, 2 Department of Pharmacy, Hefei Fourth People’s
Hospital, Hefei, China, 3 Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China, 4 Anhui
Clinical Research Center for Mental Diseases, Hefei, China

The lack of biomarkers greatly limits the diagnosis and treatment of major depressive
disorder (MDD). Endogenous L-carnitine (LC) and its derivative acetyl-L-carnitine
(ALC) play antidepressant roles by improving brain energy metabolism, regulating
neurotransmitters and neural plasticity. The levels of ALC in people and rodents with
depression are significantly reduced. It is necessary to determine whether serum LC
and ALC might be used as novel biomarkers for the diagnosis of MDD. Here, ultra-high
performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was
Edited by: used to determine the concentration of LC and ALC in the serum of healthy controls and
Agorastos Agorastos, patients with MDD; among the latter, in patients who were responsive (effective group)
Aristotle University of
Thessaloniki, Greece and non-responsive (ineffective group) after 2 weeks of treatment. The diagnostic value
Reviewed by: of serum LC and ALC for MDD was assessed. Compared with healthy controls, the
Carla Nasca, serum LC and ALC concentrations in patients with MDD were significantly decreased (P
The Rockefeller University,
< 0.001). Pearson correlation analysis shows that the HDRS-24 score was negatively
United States
Aleksander A. Mathé, associated with serum ALC (r = −0.325, P = 0.007). Receiver operating characteristic
Karolinska Institutet (KI), Sweden (ROC) analysis revealed an area under the curve (AUC) of 0.801 with 83.1% sensitivity
*Correspondence: and 66.3% specificity for LC, and an AUC of 0.898 with 88.8% sensitivity and 76.4%
Qing-Rong Xia
[email protected] specificity for ALC, differentiating patients with MDD from healthy controls. Furthermore,
the concentration of LC and ALC in patients with depression was significantly increased
Specialty section: in the effective treatment group, and no significant change was observed in the ineffective
This article was submitted to
Mood and Anxiety Disorders,
treatment group. These results suggest that serum LC and ALC may be novel biomarkers
a section of the journal for the diagnosis of MDD.
Frontiers in Psychiatry
Keywords: biomarker, acetyl-l-carnitine, diagnosis, depression, L-Carnitine
Received: 23 February 2021
Accepted: 02 September 2021
Published: 30 September 2021
INTRODUCTION
Citation:
Nie L-J, Liang J, Shan F, Wang B-S,
Major depressive disorder (MDD) is a common mental disorder that is the leading cause of
Mu Y-Y, Zhou X-H and Xia Q-R (2021)
L-Carnitine and Acetyl-L-Carnitine:
disability around the World (1, 2). According to a recent survey, the lifetime and 12-month
Potential Novel Biomarkers for Major prevalence rates of depression in China are 3.4 and 2.1%, respectively (3). The pathogenesis
Depressive Disorder. of the disease is relatively complex, which is generally considered to be related to genetics,
Front. Psychiatry 12:671151. sex, neuroendocrine, psychosocial environment, immunity, intestinal microorganisms, and other
doi: 10.3389/fpsyt.2021.671151 factors (4–6). At present, clinical diagnosis is mainly based on the description of symptoms by

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Nie et al. L-Carnitine Acetyl-L-Carnitine Biomarkers for Depression

the patient, mental state examination, and clinical behavior MATERIALS AND METHODS
observation, lacking objective diagnosis indicators (7–9), which
greatly increases the incorrect diagnosis. The effect of drug Participants
therapy is not obvious in some patients, which is also related A total of 261 individuals with a first depression episode
to incorrect diagnosis (10). Therefore, it is of great significance (according to the Diagnostic and Statistical Manual for
to explore the pathogenesis of depression and search for Psychiatric Disorders, fourth edition) hospitalized at the Anhui
biomarkers for the diagnosis and diversified treatment of Mental Health Center from November 2018 to October 2020,
clinical depression. were scanned in this study, 89 patients with MDD were selected.
Studies have shown that neuroplasticity impairment may be The inclusion criteria were as follows: the age ranged from 18
the significant pathophysiological mechanism of depression (11, to 70 years; a primary diagnosis of MDD in a current major
12). In addition, studies demonstrated that acetyl-L-carnitine depressive episode; the reduction rate of the 24-item Hamilton
(ALC) has multiple functions related to neuroplasticity (13) and Depression-Rating Scale (HDRS-24) score in the treatment-
is an antidepressant substance with significant potential. ALC effective group was ≥50% and the reduction rate of HDRS-
is a natural form of L-carnitine (LC). High concentrations of 24 score in the treatment-ineffective group was <50% (33). A
carnitines either free carnitine or as acylcarnitines including significant improvement in patients’ depressive symptoms was
ALC, are present in biological tissues and cells (14). ALC is observed after treatment in the effective-treatment group. The
an endogenous compound, and it is mainly present in brain, exclusion criteria were as follows: alcohol and drug abusers; use of
kidney, and liver. Its main physiological function is to promote immunomodulators, various antidepressants, or lithium salts in
coenzyme A to enter into the mitochondria, thus promoting β- the last half year; history of serious heart, liver, kidney, and other
oxidation of long-chain fatty acids (15). In addition to improving serious body diseases, metabolic diseases, and infectious diseases
mitochondrial function and energy, and enhancing antioxidant such as cold and fever in the last 2 weeks; combination with other
activity (16), ALC has been shown to be effective in a variety mental illness or nervous system disease history; pregnancy and
of neuropsychiatric disorders, such as Alzheimer’s disease (17, lactation. The healthy control (HC) individuals were recruited
18), attention deficit hyperactivity disorder (19), depression from the Anhui Medical University Health Checkup Center. HC
(20) and depressive symptoms in the course of fibromyalgia were free of lifelong mental and major illnesses and metabolic
(21), multiple sclerosis (22), and alcohol dependence (23). In diseases. The subjects had no active infections and systemic
addition, animal studies (24–26) have shown that, in rodents diseases confirmed by the medical history at the time of the
with depression-like characteristics, ALC levels were significantly study evaluation. Blood samples were collected from the vein
reduced, ALC supplementation can induce rapid and durable through standard techniques before the evaluation meeting and
antidepressant-like effects through the epigenetic mechanism of all subjects were fasting. Tubes with a 5 mL capacity were used
histone acetylation, antidepressant responses were seen after 3 to collect the blood. Samples were centrifuged at 3,000 r/min
d that also last for 14 d after drug withdrawal. The clinical for 5 min at 4◦ C and the serum was collected. The serum was
research results (27, 28) showed that serum ALC levels in patients stored at −80◦ C for further use. According to the principles of the
with severe depression are significantly lower than those in Declaration of Helsinki, all subjects provided informed written
healthy people, and ALC supplementation significantly reduced consent before participating. This study was approved by the
depressive symptoms. Ethics Committee of the Anhui Provincial Mental Health Center.
Acetyl-CoA and LC in the body are synthesized into ALC All our researches have been adhered to standard biosecurity and
by carnitine acetyltransferase catalyzed. LC is also involved institutional safety procedures.
in the β-oxidation pathway. The deficit of LC can result Clinical assessment consisted of a physical examination,
in impairment of β-oxidation, which in turn leads to the including measures of height, weight, body mass index (BMI),
consumption of acetyl-CoA, and ultimately leads to the reduction and biochemical indexes. Additional information was collected,
of ALC production (29). There is also a certain relationship including demographics, current drug use, Hamilton Anxiety
between LC and depression. Studies (30, 31) have reported Scale (HAMA) score and HDRS-24 score. Regarding drug use,
that serum free carnitine levels were significantly reduced in 89 patients with a first depression episode did not take any
patients undergoing hemodialysis treatment, and free carnitine antidepressants while they participated in the study. In addition,
levels with a low baseline level are independently associated we evaluated the LC and ALC levels of 55 patients after treatment.
with the severity of depression in male patients. Clinical studies Blood samples were collected through the vein 2–6 weeks after
(31, 32) have shown that L-carnitine supplementation can treatment, and were divided into treatment-effective group and
improve the depression state of male uremic patients and treatment-ineffective group according to the HDRS-24 score
cancer patients. reduction rate.
Therefore, we aimed to apply UPLC-MS/MS method to
determine the concentrations of LC and ALC in serum, compare UPLC-MS/MS Determination of LC and
the differences in the levels of LC and ALC between MDD ALC
patients and healthy controls; analyze the levels of LC and A simple, rapid, and selective UPLC-MS/MS method for the
ALC correlation with the degree of depression; and study determination of LC and ALC in human serum was developed.
the role of ALC and LC levels in the onset and diagnosis The UPLC-MS/MS instrumentation was composed of a Waters
of depression. Acquity ultra performance liquid chromatography (UPLC) I

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Nie et al. L-Carnitine Acetyl-L-Carnitine Biomarkers for Depression

TABLE 1 | Comparison of age, gender, and BMI between the MDD and the HC
groups (mean ± SD).

Variables MDD group HC group Test (t or χ 2 ) P-value

Age 36.92 ± 16.34 37.00 ± 15.22 −0.033 0.974

Gender (female/male) 57/32 58/31 0.025a 0.875
BMI (kg/m²) 21.58 ± 3.51 22.30 ± 3.49 −1.378 0.170

a Indicates χ2 score. P < 0.05 was considered statistically significant.

Class Binary Solvent Manager, Acquity UPLC Sample Manager-

FTN coupled to a Waters Xevo TQ-S mass spectrometer
(Waters, Massachusetts, USA). Acetyl-L-carnitine-d3 (ALC-
d3 ) was selected as the internal standard (IS). After protein
precipitation with acetonitrile-water (1 mL, 2:1, v/v), the analytes
and IS were separated on a 2.5 µm Waters XSelect HSS T3
C18 column through gradient elution with methanol-water
(containing 0.01% aqueous ammonia) as the mobile phase at a
flow rate of 0.2 mL/min. Analytes were detected with multiple
reaction monitoring using a positive scan mode with electrospray
ionization (ESI). The ratios of signal intensities for the transitions
m/z 162.10 > 102.97 (LC), m/z 204.14 > 85.03 (ALC), and
207.19 > 85.03 (ALC-d3 ) were converted to concentration
using a calibration curve. ALC hydrochloride (>98% purity)
was purchased from Sigma-Aldrich (St. Louis, MO, USA). L-
carnitine·HCl (>98% purity) and ALC-d3 ·HCl (>98% purity) FIGURE 1 | Decreased acetyl-L-carnitine (ALC) and L-carnitine (LC) levels in
were purchased from Toronto Research Chemicals Inc. (TRC, patients with MDD compared to those in the HC group. (A) Serum LC
North York, Canada). All the other analytical reagents and concentrations in HC and patients with MDD; (B) ALC concentrations in HC
solvents were above chromatographic purity level. A quality and patients with MDD. P < 0.001 was considered statistically significant.
Dashed bars indicate group mean.
control was conducted for each experiment to ensure the
accuracy of the results.

Statistical Analysis
All statistical analyses were conducted using the SPSS version patients with MDD (n = 89) (Table 1). All the patients were
17.0 (SPSS, Chicago, Illinois, USA). Student’s t-test and χ 2 in an acute depressive episode during study participation. The
analysis were used to compare the continuous and classified level of LC in the MDD group was lower than that in the HC
demography and clinical characteristics of HC and patients (Figure 1A, P < 0.001, t = 8.01, effect size = 1.20, Power =1.00,
with MDD. The serum LC and ALC concentrations of all HC: 6.64 µg/mL ± 1.20, MDD: 5.12 µg/mL ± 1.33). Similarly,
the individuals in the HC and MDD groups were compared the level of ALC in the MDD group was significantly lower
with an independent-sample t-test and the serum LC and than that in the HC group (Figure 1B, P < 0.001, t = 9.93,
ALC concentrations of MDD before and after treatment were effect size = 1.49, Power = 1.00, HC: 3.05 µg/mL ± 1.30, MDD:
compared with a paired-sample t-test. The relation between 1.54 µg/mL ± 0.60).
HDRS-24 scores and the other variables were analyzed with In patients with moderate to severe MDD (HDRS-24 score
Pearson correlation tests and the independent relationships > 24), ALC levels were significantly negatively correlated with
were determined by multivariate linear regression analysis. The severity scores: the higher the severity, the lower the ALC
receiver operating characteristic (ROC) curve analysis was used concentrations (r = −0.325, P = 0.007) (Figure 2). In the
to determine the area under the curve (AUC) and cut-off values multiple regression analysis controlling for BMI value, gender,
of serum LC and ALC. P < 0.05 was considered statistically and age, this relationship was still significant (t = −2.79, P =
significant. Unless otherwise specified, the data are expressed as 0.007). No correlation was found between LC concentration and
mean ± SD. HDRS-24 scores (r = −0.135, P = 0.271).
In addition, the ROC curve analysis showed potential
RESULTS diagnostic values of serum ALC and LC (Figure 3). The AUC
of LC and ALC were 0.801 and 0.898, respectively. When the
LC and ALC Levels Differ Between Healthy critical value of LC was 5.52 µg/mL, the sensitivity and specificity
Controls and Patients With MDD of MDD patients and HC were 83.1 and 66.3%, respectively. At
There were no differences in age, BMI, gender, and other the ALC critical concentration of 1.835 µg/mL, the sensitivity was
demographic characteristics between the HC (n = 89) and 88.8%, and the specificity was 76.4%. When the LC and ALC

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Nie et al. L-Carnitine Acetyl-L-Carnitine Biomarkers for Depression

ALC and LC Levels Differ Before and After

Treatment
Since the collection of blood samples after treatment was
not considered at the beginning of the study, as well as
the impact of the new coronary pneumonia epidemic and
the time of hospitalization for <2 weeks, blood samples of
34 patients were not collected after treatment. Finally, from
June 2019 to October 2020, sera were collected from 38
patients with effective treatment and 17 patients with ineffective
treatment. There were no differences in age, BMI, gender,
HDRS-24 scores before treatment, treatment days and other
demographic characteristics between the effective-treatment and
ineffective-treatment groups, there was significant difference in
the reduction rate of HDRS-24 scores and HDRS-24 scores
after treatment between the two groups (Table 2). Additionally,
the results of covariance analysis showed that the difference of
reduction rate of HDRS-24 scores between effective group and
ineffective group was not affected by treatment days and the
HDRS-24 scores before treatment (F = 17.26, P < 0.001). In
the effective-treatment group, the LC levels were significantly
higher after treatment compared to those before treatment (t =
−3.53, P = 0.001, size effect = 0.53) (Table 3). Similarly, the ALC
levels were significantly higher after treatment than those before
treatment (t = −2.05, P = 0.047, size effect = 0.32) (Table 3). The
LC and ALC levels in the ineffective-treatment group were not
significantly increased after treatment (detailed results are shown
FIGURE 2 | Correlation between HDRS-24 scores and serum concentrations
in Table 3).
of ALC (A) and LC (B) in patients with MDD. P < 0.05 was considered
statistically significant.

DISCUSSION
LC is a non-essential amino acid derived from the essential
amino acids lysine and methionine, whose balance is maintained
through dietary intake and endogenous formation followed
by renal excretion (29). In the brain, LC and its derivative
ALC are present in high concentration, reducing nerve
damage by regulating mitochondrial permeability and preventing
excitatory toxicity (34). LC and ALC may play antidepressant
roles by improving brain energy metabolism (35), regulating
neurotransmitters (36, 37), and neural plasticity (38–40). In
agreement with the results obtained using a depression rodent
model and clinical MDD samples studied by Nasca et al. (27), the
ALC level in patients with MDD was significantly lower than that
of the age- and gender-matched HC group. Similarly, consistent
with their findings, we also found a negative correlation between
ALC level and HDRS-24 score. It is worth noting that a previous
article reported positive correlation between peripheral and
central nervous system ALC concentrations (14). Based on the
ROC analysis, the serum ALC cut-off point of 1.835 µg/mL
FIGURE 3 | ROC curve for serum ALC and LC in the identification of patients
showed a 88.8% sensitivity and a 76.4% specificity, indicating that
with MDD. AUC, area under curve; MDD, major depressive disorder; ROC,
Receiver operating characteristic.
serum ALC has a superior diagnostic value (AUC = 0.898) in
MDD. These results suggest that ALC may be a diagnostic marker
of depression.
In contrast to the above-mentioned clinical study (27),
results were considered together, the ROC analysis showed that we found that LC levels in MDD patients were significantly
the AUC of patients with MDD and HC was 0.891, the sensitivity lower than those in HC group. This difference may result
was 82.0%, and the specificity was 82.0%. from race, sample size, and eating habits. ROC curve analysis

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Nie et al. L-Carnitine Acetyl-L-Carnitine Biomarkers for Depression

TABLE 2 | Comparison of age, gender, BMI and the reduction rate of HDRS-24 scores between effective-treatment and ineffective-treatment groups (mean ± SD).

Variables Effective-treatment group Ineffective-treatment group Test (t or χ 2 ) P-value

Age 37.08 ± 16.91 38.82 ± 22.86 −0.316 0.753

Gender (female/male) 23/15 10/7 0.014a 1.000
BMI (kg/m²) 21.12 ± 3.45 20.19 ± 3.62 0.916 0.364
HDRS-24 scores
Before treatment 34.11 ± 8.63 31.59 ± 9.98 0.953 0.345
After treatment 7.42 ± 5.77 20.88 ± 6.02 −7.888 <0.001
Treatment days 23.42 ± 10.24 19.35 ± 6.69 1.752 0.087
Reduction rate of HDRS-24 scores (%) 79.08 ± 15.06 31.59 ± 15.74 10.657 <0.001

a Indicates χ2 score.

P < 0.05 was considered statistically significant.

TABLE 3 | Comparison of serum concentrations of LC (µg/mL) and ALC (µg/mL) before and after treatment (mean ± SD).

Variables Before treatment After treatment Statistics P-value Effect size Power

Effective treatment group (n = 38) LC 5.11 ± 1.45 5.98 ± 1.76 −3.530 0.001** 0.53 0.99
ALC 1.79 ± 0.69 2.06 ± 0.91 −2.050 0.047* 0.32 0.86
LC+ALC 6.90 ± 1.78 8.04 ± 2.22 −3.607 0.001** 0.56 0.99
Ineffective- treatment group (n = 17) LC 5.25 ± 1.23 5.22 ± 1.38 0.111 0.913
ALC 2.01 ± 0.54 1.70 ± 0.58 1.643 0.120
LC+ALC 7.26 ± 1.35 6.92 ± 1.69 1.165 0.261

** P < 0.01, * P < 0.05 were considered statistically significant.

showed that the AUC of LC was 0.801. These results showed Many clinical studies (44, 45) have confirmed that, compared
that LC was closely related to depression and had good with established antidepressants, ALC can significantly reduce
diagnostic value for MDD. Pearson correlation analysis showed depressive symptoms and have similar effects. However, no
that HDRS-24 scores had no correlation with serum LC studies have reported the changes of LC and ALC levels in
concentration, which may be because ∼75% of human carnitine patients after antidepressant treatment. To verify the correlation
comes from exogenous sources (mainly from meat and dairy between the levels of LC and ALC and the outcome of depression,
products), and L-carnitine does not cross the blood-brain we compared the changes of LC and ALC in patients with
barrier directly to exert antidepressant effects like acetyl-L- depression before and after treatment. In the treatment group
carnitine. Carnitine acetyltransferase catalyzes the synthesis of where the HDRS-24 score reduction rate was >50%, the content
ALC from acetyl-CoA (CoA) and LC on the inner membrane of LC and ALC increased significantly after antidepressant
of mitochondria, and enters the mitochondrial matrix through treatment. The concentrations of LC and ALC in the ineffective
carnitine/acetylcarnitine acyltransferase. Carnitine penetrates treatment group did not change significantly. Perhaps due to
into the mitochondrial matrix, and carnitine acetyltransferase the small sample size, we did not find a difference in ALC
converts ALC into LC and acetyl-CoA (41). Because LC and ALC and LC levels between the effective and ineffective groups,
are transformed into each other in the body, the LC and ALC but the changes in ALC and LC before and after treatment
contents were positively correlated (MDD: r = 0.273, P = 0.01, were significantly different between the two groups. These
HC: r = 0.293, P = 0.005), many studies have officially confirmed results indicate that LC and ALC levels are related to the
that LC and ALC have a synergistic effect on the treatment of occurrence and efficacy of depression, but further studies are
diseases (42, 43), and ROC analysis showed that AUC of patients needed to prove it. We did not intervene in clinical drug
with MDD and HC was 0.891 when LC and ALC were considered treatment. Due to the large number of therapeutic drugs and
together. LC and ALC may therefore be considered potential the small sample size, we did not classify and describe the
biomarkers of depression simultaneously. In order to avoid the therapeutic drugs in detail, nor did we consider the impact of
effect of the drug on the baseline carnitine content, the patients different drugs on the level of carnitine after treatment. Next,
enrolled in the group were all patients with first-onset depression we hope to further expand the sample size to compare the
who had not undergone drug treatment. Further studies are effects of different types of antidepressants on the LC and ALC
needed to assess whether reduced LC and ALC levels in MDD concentrations in patients with depression and the effects of
patients are sensitive to unhealthy lifestyle choices such as lack of different baseline LC and ALC concentrations on the efficacy
exercise, poor diet, smoking, drugs and lack of sleep. of antidepressants.

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Nie et al. L-Carnitine Acetyl-L-Carnitine Biomarkers for Depression

This study has several limitations. First, the study was a AUTHOR CONTRIBUTIONS
single-center study with a small sample size; the samples after
treatment were not grouped in detail. Second, the effects of Q-RX, JL, and L-JN designed the study, wrote the protocol,
diet, exercise, sleep, and other external factors on LC and ALC and performed the statistical analysis. Q-RX carried out the
concentrations were not considered. Third, the effects of different study and collected important background information. L-JN
drugs on the LC and ALC concentrations after treatment were performed the experiments and drafted the manuscript. FS and
not considered. B-SW carried out the concepts, design, definition of intellectual
In conclusion, the detection of serum LC and ALC may content, literature search, data acquisition, data analysis, and
prove to have clinical value in the diagnosis of MDD. manuscript preparation. Y-YM and X-HZ provided assistance for
Multicenter and longitudinal studies are clearly needed to data analysis and performed the experiments. All authors have
validate the potential of LC and ALC as novel biomarkers read and approved the final manuscript.
for MDD.
FUNDING
DATA AVAILABILITY STATEMENT
This project was supported by the Anhui Medical University
The raw data supporting the conclusions of this article will be (Grant No. 2019xkj201), the Hefei Health Applied Medicine
made available by the authors, without undue reservation. (Grant No. hwk2019yb011), and the Hefei Sixth-cycle Key
Medical Specialty.
ETHICS STATEMENT
ACKNOWLEDGMENTS
The studies involving human participants were reviewed and
approved by Ethics Committee of the Anhui Provincial Mental We would like to thank Dr. Ai-Ping Wang for critical reading
Health Center. The patients/participants provided their written of the manuscript and Editage (www.editage.cn) for English
informed consent to participate in this study. language editing.

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uremic male patients undergoing hemodialysis. Lett Drug Des Discov. (2017) absence of any commercial or financial relationships that could be construed as a
14:737–42. doi: 10.2174/1570180814666170216102632 potential conflict of interest.
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neuroprotection in developing brain. Neurochem Res. (2017) 42:1661– article distributed under the terms of the Creative Commons Attribution License (CC
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and serotonin content in healthy mice. Neurochem Int. (2012) 61:100– No use, distribution or reproduction is permitted which does not comply with these
7. doi: 10.1016/j.neuint.2012.04.008 terms.

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