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Tesi etd-10062014-120959

Thesis type
Tesi di laurea specialistica LC5
Alterations of hippocampal neurogenesis in a mouse model of X-linked intellectual disability
Corso di studi
relatore Caleo, Matteo
relatore Prof. Demontis, Gian Carlo
Parole chiave
  • intellectual disability
  • hippocampus
  • neurogenesis
Data inizio appello
Riassunto analitico
Intellectual disability (ID) is a complex disease of the central nervous system<br>(CNS). The genetic contribution to the etiology of ID is well established and, among<br>the genetic conditions, the most frequent are the X-linked intellectual disability<br>(XLID) forms. Among the XLID genes, Oligophrenin-1 (OPHN-1) encodes a synaptic<br>Rho GTPase- activating protein that regulates neuronal morphology, proliferation<br>and maturation. The involvement of OPHN-1 in XLID was well established by the<br>identification of mutations within the gene, in patients with XLID. OPHN-1 gene is<br>expressed in brain areas that are characterized by high synaptic plasticity: in particular,<br>the olfactory bulb and the hippocampus. However, it is not clear how mutations<br>in OPHN1 result in impaired neuronal development and consequent cognitive<br>deficits.<br>To address these issues, I have used a mouse model of XLID based on germline<br>deletion of the OPHN1 gene (OPHN1 KO; Khelfaoui et al., J Neurosci 2007). In particular,<br>as adult hippocampal neurogenesis recapitulates the processes of neuronal<br>differentiation, I have studied the development of newborn cells in the hippocampus<br>of wt and OPHN1 KO mice. Using labelling of newborn cells with the thymidine analogue<br>bromo-deoxy-uridine (BrdU), I found that cell proliferation in the subgranular<br>zone of the hippocampus was not impacted by OPHN1 deficiency. Importantly, reduced<br>numbers of BrdU-positive neurons were found 50 days after BrdU pulse labelling<br>in OPHN1 KO mice, indicating impaired neuronal differentiation. In keeping<br>with these data, the number of migrating neuroblasts (stained with a doublecortin –<br>Dcx -antibody) was also decreased in the dentate gyrus of KO animals. We also<br>found reduced numbers of cells double positive for Dcx and the neuronal marker<br>NeuN, confirming the impaired integration of newborn neurons in the hippocampus<br>of OPHN1 KO mice.!<br>Prompted by these results, we tested a novel therapeutic strategy based on inhibition<br>of the RhoA pathway, whose activity is potently stimulated by loss of OPHN-1.<br>In particular, we administered via the drinking water fasudil, an inhibitor of the<br>ROCK kinase. Preliminary data indicate that fasudil treatment restores normal<br>numbers of Dcx-NeuN double positive cells in the hippocampus of OPHN1 KO<br>animals. !<br>Altogether, these data demonstrate robust alterations in hippocampal neurogenesis<br>in OPHN1 mice, and suggest a possible strategy for counteracting defects in neuronal<br>differentiation triggered by loss of OPHN1.