Morfološke promjene projekcijskih neurona strijatuma u miša s humaniziranim oblikom gena Foxp2 [Changes in morphology of projection striatal neurons in mice with humanized version of Foxp2 gene]

Bičanić, Ivana (2017) Morfološke promjene projekcijskih neurona strijatuma u miša s humaniziranim oblikom gena Foxp2 [Changes in morphology of projection striatal neurons in mice with humanized version of Foxp2 gene]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

It has been proposed that the FOXP2 gene has an important role in the function of neural circuitries involved in speech processing. A protein coded by this gene differs between chimpanzee and man in only two amino acids, which means that it is extremely conserved. Individuals with only one functional FOXP2 allele suffer from speech impairment and have structural changes predominantly found in the striatum. When a human variant of the gene was experimentally introduced into the Foxp2 gene of mice, experiments showed that this gene caused electrophysiological as well as different behavioural changes in the experimental animals. Research studies implicated its role in dendritic outgrowth of neurons that highly express Foxp2, like medium spiny neurons of striatum. The goal of this research was to analyse the morphology of medium spiny neurons in the wild type animals using Golgi-Cox method, to determine regional differences in their morphology throughout dorsal striatum and to see the possible effect of humanized Foxp2 gene and two additional lines of transgenic animals (Foxp2T302N and Foxp2N324S) on their morphology. The results showed that there were no major morphological differences between the neurons of transgenic animals and their control group but there were regional differences in neuronal morphology, especially in the rostral and caudal striatum where the neurons had on average 15-20% greater dendritic trees but with different topology. Accordingly, the number of segments was proportionally increased in the caudal parts, as opposed to the rostral parts that had longer average length of individual segments. Although these differences were not significant, they implied structural changes influenced by Foxp2 gene, which were not directly related to dendritic outgrowth but rather with changes in activity of the corticostriatal loops associated with frontal and occipital cortex. The results showed that in order to influence changes present in the humanized animals, both amino acid changes in the protein structure are needed.

Abstract in Croatian

Smatra se da FOXP2 gen ima važnu ulogu u neuralnim krugovima koji omogućavaju procesiranje govora. Protein koji kodira taj gen se između čimpanze i čovjeka razlikuje u samo dvije aminokiseline što govori u prilog njegove visoke konzerviranosti. U ljudi sa samo jednim funkcionalnim alelom FOXP2 gena najizraženije strukturne promjene se nalaze u strijatumu, što korelira s poremećajima govora. Transgenična varijanta čovječjeg gena dovela je u miša do različitih elektrofizioloških promjena i promjena u ponašanju. Dosadašnja istraživanja su implicirala i njegov utjecaj na rast dendritičkog stabla u neuronima u kojih je izraženost Foxp2 najveća, a to su trnasti srednje veliki neuroni strijatuma. Cilj ovoga istraživanja je bio detaljno analizirati morfologiju trnastih srednje velikih neurona strijatuma u miševa divljeg tipa koristeći Golgi Cox metodu, utvrditi regionalne razlike u morfologiji unutar strijatuma te vidjeti kako na njihovu morfologiju utječe humanizirani Foxp2 gen i njegove dvije varijante (Foxp2T302N i Foxp2N324S). Naše istraživanje je pokazalo da između transgeničnih životinja i njihovih kontrolnih skupina nije bilo značajnijih razlika u neuronalnoj morfologiji, no uočene su regionalne razlike i to osobito u rostralnom i kaudalnom dijelu strijatuma gdje neuroni u prosjeku imaju 15-20% veće dendritičko stablo, ali uz različitu topologiju. Tako se u kaudalnim dijelovima proporcionalno povećava broj segmenata, dok u rostralnim dijelovima to nije slučaj pa su u prosjeku pojedinačni segmenti značajno duži. Iako razlike nisu značajne, one ukazuju na to da promjene u strukturi ovog gena nisu izravno povezane s izrastanjem dendrita, već da dolazi do promjene aktivnosti kortiko-strijatalnih krugova povezanih s čeonom i zatiljnom moždanom korom. U linijama miševa koje nose samo jednu zamijenjenu aminokiselinu nisu uočene značajne razlike u morfologiji dendritičkog stabla. Dobiveni rezultati ukazuju da su promjene koje se mogu pripisati humaniziranom obliku Foxp2 gena vezane uz potrebu zamjene obje aminokiseline u njegovom proteinu.

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