Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

Full Study: [Brain-derived neurotrophic factor \(BDNF\) overexpression in the forebrain results in
learning and memory impairments](https://mega.nz/#!4R53RbBK!L_Yy4H24mQ8TlhKA2nlCpOtTFLTv6nFXixyKlExblhw)

>What may be the cellular basis for such detrimental effect of
BDNF overexpression on learning? In a recent publication it has been
shown that the same BDNF line we used manifests anxiety-like
behavior with a concomitant increase in spine density in the
basolateral amygdala. In contrast, upon chronic stress, such over-
expression appears to prevent atrophy in the hippocampus a cellular
phenotype likely linked to the antidepressant effect observed in the
forced swim test (Govindarajan et al., 2006). Considering these
recent findings, the explanation of the observed learning deficits is
likely to be a complex one, possibly involving also motivational
aspects of behavior.

>The hypothesis we tend to favor is instead that an excess of mature
BDNF may preferentially act on inhibitory interneurons, thus leading
to a general alteration of the inhibitory tone of the synaptic circuitry
underlying learning. Indeed, TrkB receptors have been found in a
number of interneurons in the forebrain and a number of functions
have been ascribed to BNDF in non pyramidal cells, including brain
diseases such as schizophrenia and epilepsy. The increased excitability
observed by Croll et al (Croll et al., 1999) may suggest that a chronic
BDNF expression could lead to a reduced inhibition by attenuating
IPSCs, as observed in a number of interneuron types upon acute BDNF administration (for review see Woo and Lu, (2006)). In addition, as a
non mutually exclusive possibility, an abnormal increase at specific
excitatory synapses that in turn inhibits the main hippocampal
circuitry cannot be in principle excluded.

Now what I am sure a lot of people are thinking is how this affects neurogenic compounds like Semax. I think the relative increases in BDNF need to be stated to put that in perspective.

> transgenic mice showed higher BDNF immunoreactivity in all forebrain structures analyzed, as compared to WT
littermates: we observed an increase of BDNF protein levels of 2.4 fold
in the striatum (10.24±0.95 vs 4.18±0.32 ng/g wt tissue; pb0.01), 3.3
fold in the hippocampus (54.36±10.68 vs 16.67±1.66 ng/g wt tissue;
pb0.01), 2.8 fold in the frontal cortex (71.30±15.71 vs 19.53±1.54 ng/g
wt tissue; pb0.05),1.8 fold in the parietal cortex (55.87±4.42 vs 31.00±
2.44 ng/g wt tissue; pb0.01) and 2.0 fold in the occipital cortex (154.30±
10.92 vs 78.67±12.46 ng/g wt tissue; pb0.01). However, BDNF protein
levels in the cerebellum were undistinguishable between transgenic and
WT mice (29.12±3.38 vs 29.41±2.03 ng/g wt tissue).

So the transgenic mice are seeing 2-4x times the expression of BDNF in multiple areas of the brain. Semax only raises levels in the hippocampus and basal forebrain.

The Heptapeptide SEMAX stimulates BDNF Expression in Different Areas of the Rat Brain in vivo

Note that, in quantitative terms, the effects of SEMAX on BDNF level were considerably different for the hippocampus and basal forebrain. For instance, while the BDNF level in the hippocampus increased under the action of the heptapeptide by 30% to 35% and by more than two times 3 and 24 h after the injection, respectively, the increase in the BDNF level in the basal forebrain was significant only 3 h after the administration of the peptide. Twenty-four hours after the peptide injection, the BDNF level in this part of the brain was the same both in the experimental and in control animals.

So while the increase in BDNF in the hippocampus is similar to the transgenic mice in the other study, the levels in the forebrain are only significantly increased for 3 hours, and are back to normal after 24hr. It's also not affecting levels in other areas of the brain.

no changes in its level were found in experimental animals' brain hemispheres or cerebellum after the injection of 50 or of 250 mg/kg of the peptide.

So this study is certainly interesting. However, its not a definitive answer to the question about how chronic use of compounds that up-regulate BDNF expression in the brain affect cognition.