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Tesi etd-10062014-120959


Tipo di tesi
Tesi di laurea specialistica LC5
Autore
AZZIMONDI, STEFANO
URN
etd-10062014-120959
Titolo
Alterations of hippocampal neurogenesis in a mouse model of X-linked intellectual disability
Struttura
FARMACIA
Corso di studi
CHIMICA E TECNOLOGIA FARMACEUTICHE
Commissione
relatore Caleo, Matteo
relatore Prof. Demontis, Gian Carlo
Parole chiave
  • intellectual disability
  • hippocampus
  • neurogenesis
Data inizio appello
12/11/2014;
Disponibilità
completa
Riassunto analitico
Intellectual disability (ID) is a complex disease of the central nervous system
(CNS). The genetic contribution to the etiology of ID is well established and, among
the genetic conditions, the most frequent are the X-linked intellectual disability
(XLID) forms. Among the XLID genes, Oligophrenin-1 (OPHN-1) encodes a synaptic
Rho GTPase- activating protein that regulates neuronal morphology, proliferation
and maturation. The involvement of OPHN-1 in XLID was well established by the
identification of mutations within the gene, in patients with XLID. OPHN-1 gene is
expressed in brain areas that are characterized by high synaptic plasticity: in particular,
the olfactory bulb and the hippocampus. However, it is not clear how mutations
in OPHN1 result in impaired neuronal development and consequent cognitive
deficits.
To address these issues, I have used a mouse model of XLID based on germline
deletion of the OPHN1 gene (OPHN1 KO; Khelfaoui et al., J Neurosci 2007). In particular,
as adult hippocampal neurogenesis recapitulates the processes of neuronal
differentiation, I have studied the development of newborn cells in the hippocampus
of wt and OPHN1 KO mice. Using labelling of newborn cells with the thymidine analogue
bromo-deoxy-uridine (BrdU), I found that cell proliferation in the subgranular
zone of the hippocampus was not impacted by OPHN1 deficiency. Importantly, reduced
numbers of BrdU-positive neurons were found 50 days after BrdU pulse labelling
in OPHN1 KO mice, indicating impaired neuronal differentiation. In keeping
with these data, the number of migrating neuroblasts (stained with a doublecortin –
Dcx -antibody) was also decreased in the dentate gyrus of KO animals. We also
found reduced numbers of cells double positive for Dcx and the neuronal marker
NeuN, confirming the impaired integration of newborn neurons in the hippocampus
of OPHN1 KO mice.!
Prompted by these results, we tested a novel therapeutic strategy based on inhibition
of the RhoA pathway, whose activity is potently stimulated by loss of OPHN-1.
In particular, we administered via the drinking water fasudil, an inhibitor of the
ROCK kinase. Preliminary data indicate that fasudil treatment restores normal
numbers of Dcx-NeuN double positive cells in the hippocampus of OPHN1 KO
animals. !
Altogether, these data demonstrate robust alterations in hippocampal neurogenesis
in OPHN1 mice, and suggest a possible strategy for counteracting defects in neuronal
differentiation triggered by loss of OPHN1.
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