Sigma-1 receptor knockout impairs neurogenesis in dentate gyrus of adult hippocampus via down-regulation of NMDA receptors - PubMed (original) (raw)

Sigma-1 receptor knockout impairs neurogenesis in dentate gyrus of adult hippocampus via down-regulation of NMDA receptors

Sha Sha et al. CNS Neurosci Ther. 2013 Sep.

Abstract

Aims: This study investigated the influence of sigma-1 receptor (σ1 R) deficiency on adult neurogenesis.

Methods: We employed 8-week-old male σ1 R knockout (σ1 R(-/-) ) mice to examine the proliferation and differentiation of progenitor cells, and the survival and neurite growth of newborn neurons in hippocampal dentate gyrus (DG).

Results: In comparison with wild-type (WT) littermates, the numbers of 24-h-old BrdU(+) cells and Ki67(+) cells in σ1 R(-/-) mice increased, while the number of 28-day-old BrdU(+) cells decreased without changes in proportion of BrdU(+) /NeuN(+) cells and BrdU(+) /GFAP(+) cells. The neurite density of newborn neurons was slightly reduced in σ1 R(-/-) mice. In DG granular cells, N-methyl-d-aspartate (NMDA)-activated current (INMDA ) and phosphorylation of NMDA receptor (NMDAr) NR2B were reduced in σ1 R(-/-) mice without the alteration of NR2B expression and membrane properties compared to WT mice. The NR2B antagonist abolished the difference in INMDA between σ1 R(-/-) mice and WT mice. The application of NMDAr agonist in σ1 R(-/-) mice prevented the over-proliferation of cells and reduction in newborn neurons, but it had no effects on the hypoplastic neurite. The administration of NMDAr antagonist in WT mice enhanced the cell proliferation and depressed the survival of newborn neurons.

Conclusion: The σ1 R deficiency impairs neurogenesis in DG through down-regulation of NMDArs.

Keywords: Hippocampus; N-methyl-d-aspartate receptor; Neurogenesis; Sigma-1 receptor; γ-Aminobutyric acid.

© 2013 John Wiley & Sons Ltd.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

The σ1

R

deficiency enhances the proliferation of progenitor cells in hippocampal dentate gyrus (

DG

). (A) Left panels represent representative images of 24‐h‐old

B

rd

U

R

−/− mice and wild‐type (

WT

) mice. Scale bar = 100 μm. Bar graph shows mean number of 24‐h‐old

B

rd

U

R

−/− mice (n = 8) and

WT

mice (n = 8). **P <0.01. (B) Representative images of

K

i67+ cells (white arrowheads) in σ1

R

−/− mice and

WT

mice. Scale bar = 50 μm. Bars indicate mean number of

K

i67+ cells in σ1

R

−/− mice (n = 8) and

WT

mice (n = 8). *P <0.05.

B

rd

U

, bromodeoxyuridine.

Figure 2

Figure 2

The σ1

R

deficiency decreases survival of newborn neurons in hippocampal dentate gyrus (

DG

). (A) Left panels represent images of 28‐day‐old

B

rd

U

R

−/− mice and wild‐type (

WT

) mice. Scale bar = 100 μm. Bar graph shows mean number of 28‐day‐old

B

rd

U

R

−/− mice (n = 8) and

WT

mice (n = 8). **P <0.01. (B, C)

B

rd

U

and

N

eu

N

or

GFAP

were double‐stained on 28th day after injection of

B

rd

U

in σ1

R

−/− mice and

WT

mice (left panel). Neurons (immunoreactive for

N

eu

N

) and glial cells (immunoreactive for

GFAP

) are shown in green, and newborn neurons (immunoreactive for both

B

rd

U

and

N

eu

N

or

GFAP

) are shown in yellow (white arrowheads). Scale bar = 50 μm. Bar graph shows the mean number of 28‐day‐old

B

rd

U

+/

N

eu

N

B

rd

U

+/

GFAP

R

−/− mice (n = 8) and

WT

mice (n = 8). **P <0.01.

B

rd

U

, bromodeoxyuridine;

GFAP

, antiglial fibrillary acidic protein.

Figure 3

Figure 3

The σ1

R

deficiency decreases neurite growth of newborn neurons in hippocampal dentate gyrus (

DG

). (A) Representative pictures of doublecortin (

DCX

) immunostaining in σ1

R

−/− mice and wild‐type (

WT

) mice. Scale bar = 50 μm. Bars indicate the mean density (B) and length (C) of

DCX

R

−/− mice (n = 8) and

WT

mice (n = 8). *P <0.05.

Figure 4

Figure 4

The σ1

R

deficiency decreases the _N_‐methyl‐

d

‐aspartate receptor (

NMDA

r) function in granular cells of hippocampal dentate gyrus (

DG

). (A) Typical traces of

_I_NMDA

in σ1

R

−/− mice and wild‐type (

WT

) mice (up panel). Bar graph shows mean density of

_I_NMDA

in σ1

R

−/− mice (n = 12) and

WT

mice (n = 12). **P <0.01. (B) Typical traces of

_I_GABA

in σ1

R

−/− mice and

WT

mice (up panel). Bar graph shows mean density of

_I_GABA

in σ1

R

−/− mice (n = 12) and

WT

mice (n = 12). (C) Typical traces of I whole in σ1

R

−/− mice and

WT

mice (up panel). Bar graph shows the maximal amplitudes of outward (

M

axoutward) and inward (

M

axinward) current in σ1

R

−/− mice (n = 12) and

WT

mice (n = 12).

Figure 5

Figure 5

The σ1

R

deficiency reduces phosphorylation of _N_‐methyl‐

d

‐aspartate receptor (

NMDA

r)

NR

2

B

. (A) The levels of NR2A and NR2B m

RNA

in hippocampal dentate gyrus (

DG

) of σ1

R

−/− mice (n = 12) and wild‐type (

WT

) mice (n = 12). (B, C) Western blots of phospho‐

NR

2

A

/2

B

and

NR

2

A

/2

B

in hippocampal

DG

of σ1

R

−/− mice and

WT

mice. The densitometric values for p

NR

2

A

and p

NR

2

B

were first normalized by the protein amounts of

NR

2

A

and

NR

2

B

, respectively, and then were normalized again by the basal values in

WT

mice, respectively. **P <0.01. (D) Bar graph shows mean density of

_I_NMDA

in σ1

R

−/− mice and

WT

mice in the presence of

NR

2

A

antagonist

NVP

‐

AMM

077,

NR

2

B

antagonist

R

o25‐6981, or

SK

channels blocker apamin, respectively (n = 12 mice in each group). **P <0.01; # P <0.05, and ## P <0.01 versus vehicle‐treated slices of

WT

mice or σ1

R

−/− mice.

Figure 6

Figure 6

The _N_‐methyl‐

d

‐aspartate receptor (

NMDA

r) agonist corrects the abnormal neurogenesis in σ1

R

−/− mice. (A, B) Bar graphs show mean numbers of 24‐h‐old

B

rd

U

B

rd

U

R

−/− mice or wild‐type (

WT

) mice treated with vehicle or

NMDA

(n = 8 mice in each group). **P <0.01; ## P <0.01 versus vehicle‐treated σ1

R

−/− mice. (C) Bars indicate the density of

DCX

R

−/− mice or

WT

mice treated with

NMDA

(n = 8 mice in each group). *P <0.05 versus vehicle‐treated

WT

mice and σ1

R

−/− mice. (D, E) Bar graphs show the numbers of 24‐h‐old

B

rd

U

B

rd

U

WT

mice treated with vehicle or

MK

801 (n = 8 mice in each group). *P <0.05.

B

rd

U

, bromodeoxyuridine;

DCX

, doublecortin.

Similar articles

Cited by

References

    1. Maurice T, Su TP, Privat A. Sigma1 (sigma 1) receptor agonists and neurosteroids attenuate β25–35‐amyloid peptide‐induced amnesia in mice through a common mechanism. Neuroscience 1998;83:413–428. - PubMed
    1. Maurice T. Beneficial effect of the sigma(1) receptor agonist PRE‐084 against the spatial learning deficits in aged rats. Eur J Pharmacol 2001;431:223–227. - PubMed
    1. Frye CA. The role of neurosteroids and nongenomic effects of progestins in the ventral tegmental area in mediating sexual receptivity of rodents. Horm Behav 2001;40:226–233. - PubMed
    1. Vallee M, Mayo W, Koob GF, Le Moal M. Neurosteroids in learning and memory processes. Int Rev Neurobiol 2001;46:273–320. - PubMed
    1. Schumacher M, Weill‐Engerer S, Liere P, et al. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog Neurobiol 2003;71:3–29. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources