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BDNF

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BDNF

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BDNF (Brain-Derived Neurotrophic Factor) is not a hormone, but a protein and neurotrophin. It acts as a growth factor (neurotrophic factor) in the brain. Learning requires neurotrophic factors.
Stress reduces BDNF in the hippocampus.
BDNF influences brain development, synaptic plasticity, learning and memory as well as other neuronal processes. BDNF promotes the function of the hippocampus.
BDNF is involved in various disorders such as depression, schizophrenia, Alzheimer’s disease, dementia, Huntington’s disease, eating disorders, Rett syndrome and epilepsy.

Whether BDNF is altered in ADHD is unclear.
Stimulant treatment restores levels of BDNF and other neurotrophic factors, which improves the ability to learn (not only school or lecture material, but also meaningful changes in one’s behavior as a result of an experience). Endurance exercise also increases BDNF. Taurine increases BDNF in the striatum.
BDNF can be influenced by factors such as learning processes, antidepressants, physical activity, dietary restriction, light and sensory stimulation.
The effect of BDNF can be altered by stress, with chronic stress reducing BDNF levels in the hippocampus and increasing them in the nucleus accumbens.

There are different receptors for BDNF, including the TrkB receptor, which has a high affinity for BDNF, and the p75 receptor, which has a low affinity for BDNF.
BDNF can freely cross the blood-brain barrier.123 The BDNF blood serum level is said to correlate with the size of the hippocampus.4

1. Control areas of BDNF

1.1. Behavioral functions

BDNF controls many behavioral functions in cooperation with serotonin.

BDNF influenced:5

  • Brain development
  • neurogenesis
    • Differentiation of hippocampal neuron precursors6
  • Processes of neuronal plasticity
    • Direct
      • Cellular processes of neuronal plasticity
    • Indirect
      • Influence on other plasticity-modifying processes
    • Short term
      • Potentiation of synaptic excitation transmission through the depolarization of postsynaptic nerve cells
      • Facilitates the release of presynaptic neurotransmitters
    • Long-term
      • Persistent change in cell excitability and synaptic plasticity7
  • Activity-dependent synaptic plasticity86
    • synaptogenesis between Ia afferents and motor neurons6
  • memory consolidation9
    • The long-term potentiation (LTP) underlying learning and memory10
    • Deactivation of the BDNF gene or the BDNF receptor in mice
      • Restricts their learning behavior11 whereby the learning time required for spatial learning was doubled12
      • Impairs long-term potentiation, which is essential for long-term memory11
      • Prevents the improvement of learning through endurance training13
      • These effects can be remedied by an external supply of BDNF7
    • GABA inhibits long-term potentiation14
  • the sensitization of nociceptive fibres6
  • visceral sensory innervation, respiratory control6

BDNF promotes hippocampal function, in particular the survival of newly formed granule cells throughout adult life.15 BDNF modulates hippocampal plasticity and hippocampus-dependent memory.16

The transcription factor Cyclic AMP response element-binding protein (CREB1) is an important regulator of BDNF-induced gene expression. BDNF stimulates the phosphorylation and activation of CREB in nerve cells.17

BDNF influences the glutamate metabolism in the brain. In around 30 % of nerve cells, glutamatergic synaptic transmission is increased by 100 ng / ml each18

  • BDNF by 143 %
  • Neurotrophin-4/5 by 170 %

cAMP rapidly increases neurotrophin-3 (= BNDF-/NT-3 = tropomyosin receptor kinase B (TrkB) = tyrosine receptor kinase B) and causes BDNF-dependent long-term potentiation in the hippocampus.19

1.2. Disorders

BDNF is involved in various disorders, e.g.

  • Depression20
    • BDNF decreases in the hippocampus
    • BDNF increased in the nucleus accumbens21
    • BDNF decreases in blood plasma22
  • ADHD
    • Contradictory results, these below
  • Schizophrenia
  • Obsessive-compulsive disorder
  • Alzheimer’s20
    • BDNF reduces23
      • In the parietal cortex,24
      • In the hippocampus and temporal cortex25
      • In the entorhinal cortex26
    • NGF (Nerve Growth Factor) was higher in the dentate gyrus26
    • NT-3 was reduced in the motor cortex26
  • Dementia
  • Huntington’s disease
  • Eating disorders
    • Anorexia nervosa
    • Bulimia nervosa
  • Rett syndrome
  • Epilepsy

2. BDNF receptors

BDNF receptors are predominantly located in memory-relevant brain regions such as the PFC and hippocampus.8

2.1. TrkB receptor (TrkB)

The TrkB receptor has a high affinity for BDNF.8

2.2. Truncated TrkB receptor (TrkB-T)

2.3. P75 receptor

The p75 receptor has a low affinity for BDNF.8

3. Change in BDNF

3.1. Stress and BDNF

3.1.1. Stress reduces BDNF in the hippocampus

Stress reduces BDNF27 and BDNF expression in the hippocampus of humans and rats. Chronic administration of antidepressants prevents this.28

BDNF was significantly reduced by singular29 such as repeated immobilization in the hippocampus and dentate gyrus, but not neurotrophin-4 or tyrosine receptor kinases (trkB or C).
In contrast, NT-3 was increased in the hippocampus and dentate gyrus, but only during repeated immobilization (chronic stress), which was probably primarily mediated by corticosterone.
The reduction in BDNF occurred (only in the dentate gyrus) even without a corticosterone response (in rats that had had their adrenal cortex removed and were therefore unable to secrete corticosterone).30

The decrease in BDNF due to stress in the hippocampus and the increase in BDFN due to stress in the paraventricular hypothalamus may decrease with age, while the changes in NGF (Nerve Growth Factor) and neurotrophin-3 (NT-3) do not appear to change with age.31

One study found that BDNF was reduced by chronic glucocorticoid administration in the PFC, but not in the dorsal hippocampus.32

3.1.2. Chronic stress increases BDNF in the nucleus accumbens

Chronic stress increases BDNF expression in the nucleus accumbens, which in turn correlates with depression-like behaviors, such as early passivity33 or social phobia,34 but only in stress-prone, not stress-resistant rats.35

BDNF is also elevated in the nucleus accumbens in people with depression.21

Stress also has significant effects on BDNF in the amygdala and PFC.15

Blocking eye activity drastically reduces BDNF in the visual cortex of the affected eye.20

3.1.3. Chronic / acute stress and gender

In female rats, chronic stress decreased BDNF in prelimbic areas of the PFC, while acute stress increased BDNF in the dentate gyrus. In males, the values remained unchanged in both cases36
BDNF is also involved in the impairment of dopamine signaling during early childhood stress caused by maternal deprivation in rats.37

3.1.4. BDNF for DAT deficiency

DAT-KO mice that do not produce dopamine transporters show massive changes in BDNF in PFC and striatum:

  • In the PFC
    • Reduced BDNF gene expression38
    • Total BDNF and BDNF exon IV mRNA levels reduced39
    • MRNA levels of BDNF exon VI unchanged39
    • Reduced mBDNF levels and reduced trkB activation39
    • Reduced activation of αCaMKII in the PFC39
  • In the dorsolateral striatum
    • MBDNF level increased in the homogenate39
    • MBDNF levels in the cytosol increased39
    • MBDNF levels in the postsynaptic density are reduced.39
    • TrkB expression in the dorsolateral striatum postsynaptically reduced39
      • TrkB is a high-affinity BNDF receptor

3.2. Further changes to BDNF

BDNF is increased by27

  • Learning processes
  • Enriched environment / complex environments40
    • Varied, stimulating environments increase BDNF in rats
  • Antidepressants
  • Physical activity
    • Endurance sports significantly increase BDNF levels in the hippocampus and cerebral cortex.414243
    • Chronic estrogen deficiency of 7 weeks (but not acute estrogen deficiency of 3 weeks) reduces the increase of BDNF by endurance exercise in mice.44
  • Dietary restriction increases BDNF in the dentate gyrus45
  • Light and the circadian rhythm of daylight alter BDNF and neurotrophin-3.
    • In darkness, BDNF is high in the hippocampus (minimum 3.5 in light, maximum 17 in darkness)4647 in the cerebellum 48 and in the suprachiasmatic nucleus (SCN). In the SCN, BDNF levels were highest at dusk and dawn. In constant darkness, a BDNF rhythm was observed in the SCN, but not in the hippocampus.49
    • Light increases, darkness decreases BDNF in the visual cortex,50 the retina and superior colliculi48 as well as in the cerebral cortex. At least in the cerebral cortex, this rhythm is modulated by noradrenaline.51
  • Sensory stimulation of tactile hairs increases BDNF in the primary sensory cortex (barrel cortex).5253
  • Taurine significantly increased BDNF levels in the striatum in both SHR and WKY rats (whether low or high dose).54

4. Gene variants of BDNF

BDNF Val/Met correlated in humans, compared to BDNF Val/Val, with

  • A poorer episodic memory
  • Abnormal hippocampal activation on fMRI
  • Less N-acetyl-aspartate (NAA) in the hippocampus.16

5. BDNF and other growth factors and dopamine

5.1. BDNF regulates dopamine in the striatum

This presentation is based on Sulzer et al 55

The neurotrophic factor BDNF acts on TrkB (and P75) receptors.
Genetic elimination (BDNF-/- mice) or strong reduction of BDNF (BDNF-/+ mice) in the brain causes5657

  • evoked dopamine release
    • significantly reduced in the NAc shell
    • significantly reduced in the dorsal striatum
    • unchanged in the NAc core
  • dramatically increased consumption of high-fat food (intake of normal food unchanged)
  • normalized consumption of high-fat food due to D1 receptor agonists
  • extracellular dopamine levels in the caudate nucleus / putamen more than doubled
  • increased increase in dopamine levels after potassium stimulation (120 mM) (10-fold) compared to wild-type controls (6-fold)
  • electrically evoked dopamine release as well as the dopamine uptake rate in the caudate nucleus / putamen reduced

BDNF administration

  • increases the DA overflow in the striatum evoked by depolarization
  • can partially restore electrically evoked dopamine in BDNF-/+ mice
  • leaves extracellular dopamine levels unchanged

5.2. GDNF regulates dopamine release and dopamine uptake in the striatum

This presentation is based on Sulzer et al 55

The neurotrophic factor GDNF can regulate striatal DA release and uptake. GDNF plays a key role in the development, maintenance and regeneration of the mesostriatal DA system.58
In vivo, GDNF injection into the NAc caused an increase in K+-triggered DA release in the caudate nucleus/putamen59 via a long-lasting increase in TH phosphorylation and presumably DA synthesis in the striatum and SNc60
GDNF increases the amount of DA released from vesicles in axonal varicosities of midbrain DA neurons.61
GDNF increases the number of DA neurons in the midbrain and terminals in the striatum, thereby increasing dopamine in the striatum.62
GDNF regulates DAT surface expression via its receptor (Ret) by means of the guanine nucleotide exchange factor protein VAV2 (from the Rho family). Mice lacking Vav2 or Ret show increased DAT activity in the NAc.62

6. BDNF altered in ADHD?

The study situation on BDNF in ADHD is contradictory. No systematic change in BDNF in ADHD appears to be recognizable. There may be a gender-specific increase only in boys.

BDNF for ADHD

  • reduced (4 studies)4163
    • Reduced in the morning and evening for ADHD-HI and ADHD-C, reduced only in the evening for ADHD-I64
    • in adults with ADHD65
  • unchanged (3 studies)66
    • BDNF, NT-3, NGF and FGF-2 (fibroblast growth factor-2) unchanged in ADHD (blood serum).67
    • BDNF and NGF in blood serum unchanged, GDNF and NTF3 increased. No correlations between serum neurotrophin levels and ADHD severity.68
  • increased (3 studies, 1 meta-study)
    • in the blood serum, as well as NGF, GDNF, galanin.6970
    • in blood plasma71 with indications of a gender-dependent distribution
    • in the blood of male ADHD sufferers, unchanged in women72

Learning problems are typical in ADHD. Reduced BDNF in the hippocampus causes learning problems. In chronic stress, however, BDNF appears to be increased in the nucleus accumbens of stress-sensitive rats (see above).

Studies on the effect of ADHD medication on BDNF

In ADHD-HI and ADHD-C, BDNF appears to be reduced in the morning and evening, while in ADHD-I it is only reduced in the evening. MPH probably does not alter BDNF in ADHD-HI and ADHD-C, whereas MPH decreased BDNF in ADHD-I.64 An increase or decrease of BDNF by MPH could be age-dependent.7374
MPH reduced the previously elevated blood serum levels of BDNF, NGF, GDNF and galanin.69
MPH increased BDNF75 in the dorsal striatum only in male rats and in the nucleus accumbens regardless of sex.7677
Rats that received MPH as young animals had higher levels of BDNF in the PFC as they aged.78
Another study found that MPH caused a significant 42% decrease in BDNF in the striatum of female rats and a significant 50.4% increase in BDNF in the striatum of male rats. BDNF in the nucleus accumbens was unchanged.79
One study found no relevant effect of MPH on BDNF receptor expression in rats.80 Another study found that chronic MPH administration (1 to 3 mg/kg) increased BDNF mRNA expression in muscleblind-like 2 (Mbnl2) knockout mice.81 Another study found increased BDNF expression in the ventral tegmentum in adult rats after combined MPH/fluoxetine administration during adolescence.82

One study compared the effect of atomoxetine and methylphenidate on BDNF:83

  • Atomoxetine
    • increased BDNF mRNA levels
      • in the hippocampus
      • in the PFC
        • Total and exon IV BDNF mRNA levels increased
        • via increased AKT and GSK3β phosphorylation
  • Methylphenidate
    • increased BDNF gene expression
      • in the nucleus accumbens
      • in the Caudat putamen
    • reduced BDNF gene expression
      • in the PFC
      • via reduced synaptic levels of trkB, the high-affinity BDNF receptor, and reduced ERK1/2 activation

Atomoxetine reduced BDNF levels in adults with SDHD only in the ADHD-I group.84
In the dentate gyrus, only MPH, but not atomoxetine, appears to increase synaptic plasticity in rats, whereby a very high dose of 10 mg/kg body weight was used here. This is 5 to 15 times the usual dose of medication.85

As a result, the effect of MPH on BDNF seems to depend on the genetic circumstances, the time of MPH administration, age, gender and brain region.

The blood serum levels of VEGF (vascular endothelial growth factor) were significantly reduced in a study on ADHD, while those of GDNF (glial-derived neurotrophic factor) were significantly increased. However, their blood values did not correlate with the symptom severity of ADHD.67 Two studies found no altered blood serum levels of VEGF,8687 or IGF-1 or HIF-1α in children with ADHD.

In rats, MPH was associated with a significant increase in GDNF in the striatum and nucleus accumbens, irrespective of gender.76

The BDNF polymorphism Val66Met correlated with:88

  • reduced volume of gray matter in PFC and limbic structures89
  • altered connectivity of the default mode network in people with ADHD90

7. Epigenetic manipulation of BDNF by HDAC inhibitors

The universal HDAC inhibitor sulforaphane increased in vitro the levels of BDNF and components of the TrkB signaling cascade in mouse primary cortical neurons and in 3xTg-AD mice. The subsequent increase in acetylation of H3 and H4 in the vicinity of the P1 promoter of the BDNF gene led to increased levels of MAP 2 and the synaptic proteins synaptophysin and PSD-95. Sulforaphane thus appears to have an epigenetic effect on BDNF.91

BDNF is also involved in the impairment of dopamine signaling during early childhood stress induced by maternal deprivation in rats. Early infant maternal deprivation increased HDAC2 and decreased H3K9ac. Subsequent elevation of the dendritic spine modulator AKAP150 decreased synaptic levels of protein kinase A and increased mBDNF. These effects were reversed in vivo by a single administration of the HDAC inhibitor CI-994.37

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