BDNF is well known for promoting survival of cholinergic neurons, and in Alzheimer disease (AD), the neurotrophin is reduced in the hippocampus (see Murray et al., 1994) and in the cortex (see Michalski and Fahnestock, 2003). Two years ago, Jaenisch and colleagues reported that wild-type Mecp2 shuts off BDNF transcription (see Chen et al., 2003). This is what makes the current finding so interesting, because one would expect that to restore normal neurodevelopment in Mecp2 mutant mice—which lack the methyl CpG binding domain—one would have to decrease BDNF levels. But hints that the Mecp2/BDNF relationship may not be so simple came when the Jaenisch team began characterizing Mecp2 mutant animals. First author Qiang Chang and colleagues found that total brain BDNF dropped in these animals just when they started showing the first symptoms of disease, at around 6-8 weeks old.

To investigate this further, the researchers asked what would happen if they reduced BDNF in normal animals. Because BDNF knockouts are lethal, Chang and colleagues addressed this question by using BDNF conditional knockouts developed a few years ago in the Jaenisch lab. These animals retain the neurotrophin during embryonic development but then lose it shortly after birth. Chang found that BDNF conditional knockout (cKO) mice recapitulated some of the symptoms of Mecp2 mutant mice, including low brain weight, reduced size of hippocampal CA2 neurons, and repetitive hind limb clasping, which is thought to mimic the hand-wringing behavior typically found in children with Rett’s. In addition, when Chang and colleagues crossed these cKO mice with Mecp2-negative animals, they found that the double knockout animals had a much shorter lifespan than wild-type or mice lacking only Mecp2. The double knockouts also had much earlier onset of locomotor symptoms.

If loss of BDNF mimics the effects of Mecp2 mutations, then might topping up levels of the neurotrophin not relieve some of the symptoms? This is exactly what Chang and colleagues found. When they made a conditional mutant mouse that overexpressed BDNF shortly after birth, then crossed this with Mecp2 mutant animals, the offspring, which produced around twice as much of the neurotrophin as normal, developed Rett-like symptoms later in life. They lived longer than the Mecp2 mutants, and the BDNF boost also increased their locomotor activity and brain weight.

The big question is why lack of the transcriptional repressor should lead to loss of BDNF in the brain in the first place, given that it has exactly the opposite effect in cultured neurons. The explanation for this seems to be related to experimental conditions. Chang and colleagues point out that in their initial experiments, the effect of Mecp2 on BDNF expression was measured in neurons that were artificially silenced. In the brain, however, neuronal activity is known to have a huge impact on BDNF expression. “Given that BDNF expression depends on neuronal activity, we favor the hypothesis that Mecp2 deficiency reduces neuronal activity, thereby indirectly causing a decreased BDNF protein level,” write the authors. In support of this, they found that the firing rate of neurons in layer five of the cortex is reduced in Mecp2 animals by about fourfold, and that overexpression of BDNF partly restored it. The next step will be to find out why Mecp2 mutations reduce neuronal activity.

Whether these latest findings have any specific relevance to AD is unclear. However, given that both BDNF and Mecp2 have been linked to various psychological and neurological disorders, the relationship between the two genes may well be worth following.—Tom Fagan.

Reference:
Chang Q, Khare G, Dani V, Nelson S, Jaenisch R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron February 2, 2006;49:341-348. Abstract