Therapeutic implications of NSCs in FXS and future aspects

The cognitive pathology of FXS has been suggested to be caused by impaired activation of mGluR5 dependent protein synthesis at the postsynaptic sites of CNS neurons (Bear et al., 2004). This leads to improper synaptic maturation of certain neurons including pyramidal neurons of the neocortex. Consequently LTP and LTD are affected in the neocortex and in the hippocampus resulting in defects in learning and memory.

Antagonists of mGluR5 have been shown to overcome some of these defects in the adult Fmr1-KO mouse brain suggesting a possible clinical use. However, our results implicate that alterations in the FMRP-deficient brain are present already during very early development. The mGluR5 receptor is already expressed in NSCs, therefore FMRP likely has an important function in regulating mGluR5 induced translation in those cells.

However, mRNA targets for FMRP in NSCs/NPCs are unknown and future studies should be directed to identify these messages. Our findings imply that antagonists for mGluR5 receptors may have to be administered already at embryonic stage and this may prove to be impossible. This information may be disappointing to FXS patients, since some of the symptoms of the disorder cannot be overcome with drug treatment at adult ages. Still the mGlur5 antagonists may provide a significant improvement to the performance and life quality of FXS patients. A novel possibility for pharmaceutical intervention in FXS was recently found. Reduced expression of PAK, which is involved in the formation of synaptic structure, was able to abolish the great majority of FXS symptoms in mice lacking FMRP (Hayashi et al., 2007). PAK is expressed during postnatal development, and therefore it may provide an interesting target for drug intervention in the adult FXS brain.

Properties of FMRP in NSCs/NPCs and their differentiation during normal brain development are only partially understood. The signaling pathways involved in neuronal and glial differentiation that should be investigated including WNT, BMP, Notch, LIF related signaling upstream of proneural genes (Ngn1, Ngn2, and Mash1) and inhibitors of proneural genes (Hes1 and Hes5). Direct or indirect connection between these factors and FMRP should be investigated. Interestingly, the mRNAs that target the important functional KH2 domain of FMRP are largely unknown, and solving these targets may provide important information about the action of FMRP in general. Furthermore, FMRP mRNA targets are unknown in the NSCs/NPCs, which are likely important during early differentiation of NSCs/NPCs, since mGluR5 is already expressed in these cells (Melchiorri et al., 2007). The function of TrkB.T1 signaling in regulating the differentiation of NSCs/NPCs is probably an important mechanism of choosing between neural and glial fate. The pathways involved are partially known, however identification of the components of the signaling pathway that promotes the glial fate in NSCs/NPCs, may provide the actual connection between BDNF/TrkB signaling and FMRP (Cheng et al., 2007).

Reduced amount of FMRP, impaired BDNF/TrkB signaling and reduced RGS4 expression are implicated in schizophrenia. This may also provide new applications for treatment of FXS, since schizophrenia is under intense investigation. Furthermore, the relationship between FMRP and BDNF/TrkB signaling should be further investigated, since BDNF/TrkB signaling is such an important survival factor for neurons of the developing and mature brain. To summarize, the early developmental aspects of any given nervous system disorder should be evaluated to design more specific and efficient drugs to be used for treating adult patients.

12. Conclusions

This thesis aimed to elucidate the role of NSCs in fragile X syndrome and to investigate the effects of impaired BDNF/TrkB signaling on NSC survival, proliferation and differentiation. Based on the findings presented in this thesis, following conclusions can be drawn:

1. Mouse and human NSCs lacking FMRP generate more neurons with short neurites and small soma size and less astrocytes than control NSCs.

2. NSCs lacking FMRP give rise to more cells responsive to mGluR activation. The responses to mGluR in differentiating cells correlate with oscillatory intracellular Ca²⁺

responses to neurotransmitters. The oscillatory response to mGluR activation was sensitive to mGluR5 antagonist suggesting alterations in cellular plasticity of a distinct cell population responding to mGluR activation in fragile X syndrome.

3. An increased number of cells expressing Tbr2 accumulates in the embryonic SVZ of Fmr1-KO mice suggesting alterations in glutamatergic neurogenesis. The aberrant cells contribute to alterations in the formation of the deeper neocortical layers in the early postnatal brain ofFmr1-KO mice.

4. RGS4 mRNA expression is decreased in the hippocampus and neocortex of the early postnatal brain ofFmr1-KO mice suggesting a role for FMRP in G-protein signaling.

5. Overexpression of the tyrosine kinase activity deficient TrkB.T1 receptor increases the proliferation of cultured NPCs and simultaneously decreases the survival of the neurosphere-forming cells. Exogenous BDNF abolishes the defects in the survival of neurosphere-forming cells, which suggests that TrkB.T1 may inhibit BDNF/TrkB signaling in NPCs by sequestering the endogenous BDNF. TrkB.T1 overexpression increases neuronal differentiation of NPCs. Neuronal apoptosis is paralleled by increase in neuronal differentiation suggesting a homeostatic feedback loop between the survival of neurons and proliferation rate of NPCs.

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In document Differentiation of neural stem cells in fragile X syndrome (sivua 85-133)