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BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype.

Lopez-Coviella I, Mellott TJ, Schnitzler AC, Blusztajn JK - PLoS ONE (2011)

Bottom Line: Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi.These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT

Background: Cholinergic projection from the septum to the hippocampus is crucial for normal cognitive function and degeneration of cells and nerve fibers within the septohippocampal pathway contributes to the pathophysiology of Alzheimer's disease. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.

Methodology/principal findings: To determine whether BMP9 could protect the adult cholinergic septohippocampal pathway from axotomy-evoked loss of the cholinergic phenotype, we performed unilateral fimbria-fornix transection in mice and treated them with a continuous intracerebroventricular infusion of BMP9 for six days. The number of choline acetyltransferase (CHAT)-positive cells was reduced by 50% in the medial septal nucleus ipsilateral to the lesion as compared to the intact, contralateral side, and BMP9 infusion prevented this loss in a dose-dependent manner. Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi. In addition, BMP9 infusion reduced bilaterally hippocampal levels of basic FGF (FGF2) protein.

Conclusions/significance: These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.

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Related in: MedlinePlus

Sections of mouse brain showing a representative image of the unilateral transection of fimbria-fornix (top panel) and the ROI stained with an anti-CHAT antibody (Bottom Panel).CHAT-positive cells are seen in the medial septum, the diagonal band and in the striatum (bottom panel). The lines show the ROI used for cell count analysis in the medial septum. The ROI was defined by a triangular shape that extended, dorso-ventrally, from the apex of the medial septum (A) to an imaginary line connecting the lower limits of the anterior commissures on each hemisphere (B) and, medio-laterally, from the midline (A) to the outer limits of the medial septal area (C and D).
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pone-0021166-g001: Sections of mouse brain showing a representative image of the unilateral transection of fimbria-fornix (top panel) and the ROI stained with an anti-CHAT antibody (Bottom Panel).CHAT-positive cells are seen in the medial septum, the diagonal band and in the striatum (bottom panel). The lines show the ROI used for cell count analysis in the medial septum. The ROI was defined by a triangular shape that extended, dorso-ventrally, from the apex of the medial septum (A) to an imaginary line connecting the lower limits of the anterior commissures on each hemisphere (B) and, medio-laterally, from the midline (A) to the outer limits of the medial septal area (C and D).

Mentions: To assess the in vivo activity of BMP9 on injured adult septal cholinergic neurons, we performed unilateral fimbria-fornix transections in mice and treated them with varying doses of BMP9 administered via continuous ICV infusion over a 6-day period. Immunohistochemical staining of the septum with an antibody for CHAT was then used to determine the effects of the lesion and of BMP9. Serial images of the septal/diagonal band area from CHAT-immunostained histological sections were processed for cell number quantification within the region of interest (ROI) encompassing the individual left and right medial septal nuclei defined by triangular shapes shown in Figure 1 as described in the methods. The ROI were analyzed for cell number in at least three non-consecutive sections per animal. As expected, multiple CHAT-immunoreactive cells within the medial septum and the diagonal band were observed. Mice subjected to the fimbria-fornix transection and infused with PBS alone, were characterized by a 50% loss in the number of the CHAT-positive cells in the medial septum ipsilateral to the lesion (Fig. 2 and 3). Sparing of the cholinergic neurons was evident with increasing doses of BMP9, and there was little or no loss of these neurons in animals receiving 15 and 38 ng/h of BMP9 (Figs. 2 and 3), indicating that BMP9 was highly effective in preventing the loss of CHAT-positive neurons whose axons had been transected. The dose-dependent and saturable action of BMP9 could be described by a rectangular hyperbola with a good fit (R2 = 0.89) and permitted the estimation of the EC50 value for BMP9 at 1 ng/h (Fig. 3).


BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype.

Lopez-Coviella I, Mellott TJ, Schnitzler AC, Blusztajn JK - PLoS ONE (2011)

Sections of mouse brain showing a representative image of the unilateral transection of fimbria-fornix (top panel) and the ROI stained with an anti-CHAT antibody (Bottom Panel).CHAT-positive cells are seen in the medial septum, the diagonal band and in the striatum (bottom panel). The lines show the ROI used for cell count analysis in the medial septum. The ROI was defined by a triangular shape that extended, dorso-ventrally, from the apex of the medial septum (A) to an imaginary line connecting the lower limits of the anterior commissures on each hemisphere (B) and, medio-laterally, from the midline (A) to the outer limits of the medial septal area (C and D).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3113905&req=5

pone-0021166-g001: Sections of mouse brain showing a representative image of the unilateral transection of fimbria-fornix (top panel) and the ROI stained with an anti-CHAT antibody (Bottom Panel).CHAT-positive cells are seen in the medial septum, the diagonal band and in the striatum (bottom panel). The lines show the ROI used for cell count analysis in the medial septum. The ROI was defined by a triangular shape that extended, dorso-ventrally, from the apex of the medial septum (A) to an imaginary line connecting the lower limits of the anterior commissures on each hemisphere (B) and, medio-laterally, from the midline (A) to the outer limits of the medial septal area (C and D).
Mentions: To assess the in vivo activity of BMP9 on injured adult septal cholinergic neurons, we performed unilateral fimbria-fornix transections in mice and treated them with varying doses of BMP9 administered via continuous ICV infusion over a 6-day period. Immunohistochemical staining of the septum with an antibody for CHAT was then used to determine the effects of the lesion and of BMP9. Serial images of the septal/diagonal band area from CHAT-immunostained histological sections were processed for cell number quantification within the region of interest (ROI) encompassing the individual left and right medial septal nuclei defined by triangular shapes shown in Figure 1 as described in the methods. The ROI were analyzed for cell number in at least three non-consecutive sections per animal. As expected, multiple CHAT-immunoreactive cells within the medial septum and the diagonal band were observed. Mice subjected to the fimbria-fornix transection and infused with PBS alone, were characterized by a 50% loss in the number of the CHAT-positive cells in the medial septum ipsilateral to the lesion (Fig. 2 and 3). Sparing of the cholinergic neurons was evident with increasing doses of BMP9, and there was little or no loss of these neurons in animals receiving 15 and 38 ng/h of BMP9 (Figs. 2 and 3), indicating that BMP9 was highly effective in preventing the loss of CHAT-positive neurons whose axons had been transected. The dose-dependent and saturable action of BMP9 could be described by a rectangular hyperbola with a good fit (R2 = 0.89) and permitted the estimation of the EC50 value for BMP9 at 1 ng/h (Fig. 3).

Bottom Line: Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi.These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT

Background: Cholinergic projection from the septum to the hippocampus is crucial for normal cognitive function and degeneration of cells and nerve fibers within the septohippocampal pathway contributes to the pathophysiology of Alzheimer's disease. Bone morphogenetic protein (BMP) 9 is a cholinergic differentiating factor during development both in vivo and in vitro.

Methodology/principal findings: To determine whether BMP9 could protect the adult cholinergic septohippocampal pathway from axotomy-evoked loss of the cholinergic phenotype, we performed unilateral fimbria-fornix transection in mice and treated them with a continuous intracerebroventricular infusion of BMP9 for six days. The number of choline acetyltransferase (CHAT)-positive cells was reduced by 50% in the medial septal nucleus ipsilateral to the lesion as compared to the intact, contralateral side, and BMP9 infusion prevented this loss in a dose-dependent manner. Moreover, BMP9 prevented most of the decline of hippocampal acetylcholine levels ipsilateral to the lesion, and markedly increased CHAT, choline transporter CHT, NGF receptors p75 (NGFR-p75) and TrkA (NTRK1), and NGF protein content in both the lesioned and unlesioned hippocampi. In addition, BMP9 infusion reduced bilaterally hippocampal levels of basic FGF (FGF2) protein.

Conclusions/significance: These data indicate that BMP9 administration can prevent lesion-evoked impairment of the cholinergic septohippocampal neurons in adult mice and, by inducing NGF, establishes a trophic environment for these cells.

Show MeSH
Related in: MedlinePlus