Kidins220 (Kinase-D interacting substrate of 220 kDa) is a scaffold transmembrane protein abundantly expressed in the nervous system. Mutations in the KIDINS220 gene have been correlated with psychiatric disorders and with the recently described SINO syndrome, characterized by spastic paraplegia, intellectual disability, syntagmus and obesity. Kidins220 is involved in several neuronal functions regulated by neurotrophic factors, including neuronal survival, differentiation and synaptic plasticity. Previous work with the complete KO mouse model for Kidins220 evidenced the crucial role of this protein in neuronal and cardiovascular development since its embryonic ablation is lethal. Thus to gain a comprehensive understanding of the role of Kidins220 in the adult mouse, a Cre/loxP based conditional KO (cKO) mouse model was generated, in which the Ca2+/ Calmodulin-dependent kinase-II (CaMKII) promoter drives Cre expression, and consequently protein deletion specifically in the postnatal forebrain. The characterization of the Kidins220 cKO model has been accomplished through diverse approaches: behavioural experiments, brain and neuron morphological analysis, molecular signalling from brain slices and cultures, protein and gene expression assessment. cKO mice display alterations in anxiety levels and social behaviour, with a clear impairment in social memory. At the morphological level, data show reduced dendritic branching in cortical and hippocampal neurons, while at the molecular level, neuronal response to brain-derived neurotrophic factor (BDNF) stimulation is blunted, as well as the mitogen-activated protein kinase (MAPK) pathway activation. The behavioural profile of these animals provides useful knowledge about the pathophysiology of Kidins220, indicating that alterations of this protein expression may have important consequences on human pathologies of the cognitive and social sphere. Some psychiatric diseases are highly inheritable, and their causes have been traced back to genetic alterations such as point mutations and epigenetic modifications. A better understanding of such inheritable traits will provide us with a better knowledge of the cellular and physiological alterations underlying the behavioural and cognitive symptomatology of patients. In this respect, the knowledge of Kidins220 function will contribute to further elucidate the neuropathological mechanisms underlying some psychiatric diseases.
|Titolo della tesi:||Characterization of the Kidins220 CaMKIICre conditional KO mouse line|
|Data di discussione:||21-feb-2019|
|Appare nelle tipologie:||Tesi di dottorato|