ROLE OF BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) IN

NEURODEVELOPMENTBY

ADESEJI WASIU ADEBAYO08/46KA006

ANA 811:MOLECULAR EMBRYOLOGY AND GENETIC ENGINERING

Department of Anatomy,University of Ilorin

2

OUTLINE INTRODUCTION BDNF GENE BDNF RECEPTORS MECHANISM OF ACTION FUNCTIONS CONCLUSION REFERENCES

3

INTRODUCTION Brain-derived neurotrophic

factor (BDNF) is a protein (Binder and Scharfman, 2004)

A member of the neurotrophin family of growth factors.

Neurotrophic factors are found in the brain and the periphery.

It was first discovered and purified from pig brain in 1982 (Barde et al., 1982).

4

BDNF GENE The BDNF protein is encoded

by a gene that is also called BDNF (Maisonpierre et al., 1991)

BDNF gene in humans is mapped to chromosome 11p (Metsis et al., 1993).

More precisely, the BDNF gene is located from base pair 27,654,892 to base pair 27,722,057 on chromosome 11

5

BDNF RECEPTORS BDNF binds at least two receptors on

the surface of cells that are capable of responding to this growth factor,

TrkB (tropomyosin-related kinase) and

LNGFR (low-affinity nerve growth factor receptor, also known as p75)

(Patapoutian and Reichardt, 2001).

6

MECHANISM OF ACTION

7

MECHANISM OF ACTION

8

LOCALIZATION OF BDNF BDNF is present in many regions of the

CNS, including the hippocampus, cerebral cortex, cerebellum, hypothalamus, substantia nigra, amygdala and spinal cord

(Zhou et al., 2004).

9

BDNF immunostaining in Basolateral Amygdaloid Nucleus (A), SPINAL CORD (B), HYPOTHALAMUS (C), and Lateral Septum (D) that are representative of the quality of immunolabeling seen throughout the CNS (bright-field illumination). Conner et al., 1997

10

Distribution of BDNF in hippocampus. A: Bright Field nissil stained. B: insitu hybrization C: immunostaining Conner et al., 1997

DG: dentate gyrus CA: Cornu AmmonisLHb: Lateral habenular nucleus

11

FUNCTIONS OF BDNF BDNF plays critical roles in many aspects of brain

development and functions, including

Cell survival, Differentiation,Migration, Development, Learning and memory Synaptic plasticity

(Zheng et al., 2012)

12

13

ROLE IN NEUROGENESIS Intraventricular BDNF application

encourages neurogenesis in several parts of the rat brain, such as striatum, septum, thalamus, and hypothalamus (Pencea, 2001).

Direct infusion into the hippocampus increases the number of granule cells in the DG (Scharfman et al., 2005).

14

Danzer et al., 2002 transfected hippocampal cells in culture with either BDNF or NGF; DG granule cells exhibited considerable axonal and dendritic branching following BDNF, but not NGF transfection.

This effect was abolished with the application of a Trk receptor tyrosine kinase inhibitor.

Demonstrating that BDNF and Trk signaling promote neurogenesis.

15

During rat development the amount and characterized distribution of BDNF, NT-3, and NGF mRNA dramatically increased between embryonic days 11 and 12, with transcripts widely distributed by embryonic day 13 (Maisonpierre et al., 1990).

This timing corresponds directly to the onset of robust neurogenesis in the peripheral and central nervous systems (Bayer and Altman, 2004).

The transcript levels continued to increase into adulthood, especially in the hippocampus (Barnabé-Heider and Miller 2003).

16

ROLE IN NEURONAL SURVIVAL AND DIFFERENTIATION

Cortical progenitor cells express BDNF and NT-3 and their associated TrkB and TrkC receptors (Barnabé-Heider and Miller, 2003).

(BDNF) has critical functions in promoting survival, expansion, and differentiation of neural stem cells (NSCs), but its downstream regulation mechanism is still not fully understood (Chen et al., 2013).

17

BDNF is essential for normal development and function of the cerebellar cortex.

In BNDF−/− mice, there was a dramatic increase in cell death

among developing granule cells, impaired development of the layers of the

cerebellar cortex, and irregular foliation in the middle and

posterior cerebellum; defects were apparent in the declival sulcus

(absent), the intercrural fissure (absent), the prepyramidal fissure (nearly absent), and uvular sulcus (nearly absent).

(Ernfors et al., 1995)

18

BDNF IN ADULT Brain-derived neurotrophic factor

(BDNF) has been implicated in regulating adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus; however, the mechanism underlying this regulation remains unclear.

19

ROLE IN NEURONAL MIGRATION Several lines of research suggest that members of

the neurotrophin family can act as motogenic factors for the migration of cortical interneurons (Friedman et al., 1998; Fukumitsu et al., 1998) and have been proposed to be pivotal in neuronal migration (Behar et al., 1997, 2000; Brunstrom et al., 1997).

Neurotrophins are widely expressed in the developing neocortex

The cognate receptors for neurotrophins, are expressed in cortical interneurons (Klein et al., 1990; Gorba and Wahle, 1999).

20

POST NATAL DEVELOPMENT

BNDF is crucial to postnatal survival, Mice that lack BDNF demonstrate severe deficiencies

in PNS development, especially with regard to afferent neurons, but exhibit comparatively mild deficiencies in CNS development (Pozzo-Miller, et al., 1999).

most BNDF−/− mice die shortly after birth, but some do survive for a month or more (Pozzo-Miller, et al., 1999).

This evidence further implicates the importance of BDNF not just to neuron development in the PNS but also to cerebellar development and function.

21

ROLE IN MEMORY AND LEARNING BDNF regulates both memory formation and

long-term potentiation (LTP), an activity dependent strengthening of synaptic efficacy (Malenka and Bear, 2004).

Two independent lines of BDNF mutant mice show severe impairments in LTP at the CA1 synapses in hippocampus (Patterson et al., 1996).

Importantly, BDNF heterozygous mutants show similar defective LTP to that of homozygous mice, indicating that full level of BDNF is required.

22

BDNF AND NEURODEGENERATIVE DISEASES Selective reduction of BDNF mRNA in the

hippocampus has been reported in Alzheimer’s disease specimens (Phillips et al., 1991; Ferrer et al., 1999)

Decreased BDNF protein has been demonstrated in the substantia nigra in Parkinson’s disease (Howells et al., 2000).

Recent work has implicated BDNF in Huntington’s disease as well (Zuccato et al., 2001).

23

CONCLUSION The importance of BDNF and its

receptor TrkB in normal neurodevelopment can not be over emphasized.

In addition to its role in pre natal development, BDNF is also important post natally functioning in memory formation, survival of adult NPCs

24

REFERENCES Barde YA, Edgar D, Thoenen H. (1982). Purification

of a new neurotrophic factor from mammalian brain. EMBO J. 1:549–553

Binder DK, Scharfman HE (2004). "Brain-derived Neurotrophic Factor". Growth Factors 22 (3): 123–31

Chen BY, Wang X, Wang ZY, Wang YZ, Chen LW, Luo ZJ. (2013). Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/β-catenin signaling pathway. J Neurosci Res. 2013 Jan;91(1):30-41. doi: 10.1002/jnr.23138

Ernfors P, Kucera J, Lee KF, Loring J, Jaenisch R (1995). "Studies on the physiological role of brain-derived neurotrophic factor and neurotrophin-3 in knockout mice". Int. J. Dev. Biol. 39 (5): 799–807.

25

REFERENCES F. Barnabé-Heider and F. D. Miller (2003). “Endogenously produced

neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways,” Journal of Neuroscience, vol. 23, no. 12, pp. 5149–5160.

H. Scharfman, J. Goodman, A. Macleod, S. Phani, C. Antonelli, and S. Croll. (2005). “Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats,” Experimental Neurology, vol. 192, no. 2, pp. 348–356.

James M. Conner, Julie C. Lauterborn, Qiao Yan, Christine M. Gall, and Silvio Varon. (1997). Distribution of Brain-Derived Neurotrophic Factor (BDNF) Protein and mRNA in the Normal Adult Rat CNS: Evidence for Anterograde Axonal Transport J. Neurosci.,17(7):2295–2313

L. D. Pozzo-Miller, W. Gottschalk, L. Zhang. (1999). “Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice,” Journal of Neuroscience, vol. 19, no. 12, pp. 4972–4983.

Maisonpierre PC, Le Beau MM, Espinosa R, Ip NY, Belluscio L, de la Monte SM. (1991). "Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structures, distributions, and chromosomal localizations". Genomics 10 (3): 558–68.

26

REFERENCES Malenka RC and Bear MF(2004). LTP and LTD: an embarrassment

of riches. Neuron 2004; 44: 5-21. Metsis M, et al., (1993). Differential usage of multiple brain-

derived neurotrophic factor promoters in the rat brain following neuronal activation. Proc Natl Acad Sci USA. 90:8802–8806.

P. C. Maisonpierre, L. Belluscio, B. Friedman. (1990). “NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression,” Neuron, vol. 5, no. 4, pp. 501–509.

Patapoutian A, Reichardt LF (2001). "Trk receptors: mediators of neurotrophin action". Curr. Opin. Neurobiol. 11 (3): 272–80.

Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC and Kandel ER. (1996). Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron; 16: 1137-1145.

S. Bayer and J. Altman. (2004) “Development of the telencephalon: neural stem cells, neurogenesis and neuronal migration,” in The Rat Nervous System, G. Paxinos, Ed., pp. 27–73, Elsevier, Waltham, Mass, USA.

27

REFERENCES S. C. Danzer, K. R. C. Crooks, D. C. Lo, and J. O.

McNamara (2002). “Increased expression of brain-derived neurotrophic factor induces formation of basal dendrites and axonal branching in dentate granule cells in hippocampal explant cultures,” Journal of Neuroscience, vol. 22, no. 22, pp. 9754–9763.

V. Pencea, K. D. Bingaman, S. J. Wiegand, and M. B. Luskin. (2001). “Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus,” Journal of Neuroscience, vol. 21, no. 17, pp. 6706–6717.

Zheng F, Wang H (2009). "NMDA-mediated and self-induced bdnf exon IV transcriptions are differentially regulated in cultured cortical neurons". Neurochem. Int. 54 (5-6): 385–92.

28

FOR LISTENING