Why could too much BDNF be detrimental in terms of depression and memory? I am interested in looking at the effects of too much BDNF and other proteins such as repressor element one silencing transcription factor (REST). Most research suggest that elevated levels are protective, however there is a small amount of research suggesting that too much (over expression) may actually be detrimental (Cunha, et al. 2009).


  Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.


I was wondering if there is any more research, or theories as to why too much of a protein that is considered to be protective could be harmful? Thank you.

References

Cunha, C., et al. (2009) Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments. Neurobiology of Disease, 33(3), pp. 358—368DOI: 10.1016/j.nbd.2008.11.004
This is a fairly open-ended question...  One example of the potentially negative consequences of overexpressed BDNF is its effect on the likelihood and frequency of epileptic seizures.

I guess the short version of this effect is that BDNF appears to promote neuronal growth, including neurogenesis, axonal and synaptic sprouting, and neuronal excitation, in exactly the areas of the brain that are associated with epilepsy.  Epileptic seizures are essentially hyper-excitations of neurons, so any factor that increases the excitability of neurons in brain areas associated with seizures can be a culprit.

A good, fairly recent, and open access review of the role of BDNF and its primary receptor TrkB in epilepsy is McNamara &amp; Scharfman (2012):


  Intrahippocampal infusion of BDNF and transgenic overexpression of
  BDNF or TrkB increase seizure susceptibility or severity. Conditional
  knockout of TrkB eliminated epileptogenesis altogether in the kindling
  model.


That is, in epileptic mice, adding BDNF increased seizure frequency, and removing it eliminated seizures entirely.  The authors suggest several mechanisms by which this might happen:


  ... long-term potentiation (LTP) of excitatory synapses between
  principal cells may contribute to limbic epileptogenesis; that
  is, potentiation of these synapses may facilitate propagation of
  seizure activity through synaptically-coupled neuronal populations
  throughout the limbic system and beyond.
  
  One interesting possibility is that enhanced TrkB activation reduces
  expression of the K-Cl cotransporter, KCC2, ... an important molecular
  and cellular mechanism contributing to limbic epilepsy.
  
  The effect of estrogen on NPY levels could be mediated by BDNF,
  because BDNF induces NPY synthesis following TrkB activation


In other words, (1) BDNF-induced LTP - the mechanism that underlies memory and learning - increases the excitability of neurons, potentially causing seizures; (2) BDNF may inhibit KCC2, itself a synpatic inhibitor, again increasing the excitability of neurons; and (3) hormone-induced BDNF may moderate neuron hyperexcitability through its effect on yet another another protein, the neurotransmitter NPY.

Another recent review, though not open access, is Iughetti et al (2018).  Similar to the previous review:


  ... BDNF has excitatory effects in neuronal cultures and animal brain
  slices.  Furthermore, both BDNF and its conjugated receptor (... TrkB)
  are increased  in animal models and humans with epilepsy, particularly
  in the temporal and hippocampal areas. Acute injection of BDNF in
  brain of mice induces seizures, which are almost or totally abolished
  [by] blocking its transcription and pathway.


The authors also implicate the effects of BDNF on axonal sprouting and neuronal hyperexcitability, KCC2 and NKCC1 downregulation, and NPY synthesis on seizure likelihood and frequency.

Neurochemistry is complex and not well understood, and there is indication that BDNF can also have protective properties against epilepsy under certain conditions (eg, long-term in low doses).  Lots more detail is available in the reviews cited.