The role of oxytocin (OXT) in controlling social behavior suggests a link to neuropsychiatric conditions in which social behavior behavior is aberrant or even absent, such as autism. Mice lacking the OXT receptor (Oxtr-/-) display an autistic-like phenotype, including deficits in social interaction, impaired cognitive flexibility (murine correlates of autism core symptoms), increased aggression and susceptibility to seizure (common co-occurring conditions). The deficit in cognitive flexibility is particularly interesting, because it is present in few animal model of autism. For this reason we decided to investigate its underlying neurobiological and molecular mechanisms. First, we compared Oxtr+/+and Oxtr-/- neuronal morphology and spine remodeling following a cognitive behavioral test. Interestingly, we highlighted, in the Oxtr-/- mice, an enhanced connectivity and overuse of the dorsolateral striatum, possibly arising from an hippocampal dysfunction, and we proposed it as substrate for habit-like symptoms and cognitive rigidity. Second, we investigated, at the molecular level, possible sources of this hippocampal dysfunction. In particular, we analyzed Oxtr-/- hippocampal neurons for the expression of proteins involved in the setting and maintenance of excitatio-inhibition (E-I) balance. We found an upregulation of several inwardly-rectifying K+ channels (belonging to Kir2 and Kir3 families), which could alter membrane excitability, and a lack of the physiological upregulation of the chloride transporter KCC2 during development, that may lead to aberrant GABAergic signaling in mature neurons. These data give important indications that the E-I balance is altered at multiple levels in Oxtr-/- hippocampal neurons, as an altered ratio between Glutamatergic and GABAergic synapses was also previously observed in these cultures. These observations are particularly intriguing, because an E-I imbalance has been frequently associated with several neurodevelopmental disorders such as autism. Third, we disclosed an OXTR-mediated pathway modulating KCC2 expression that may restore a correct E-I balance in hippocampal neurons. All this information could be useful to understand the pathophysiology of cognitive rigidity and to develop new therapies addressing specific symptoms of autism.

NEURONAL MORPHOLOGY AND EXCITATION/INHIBITION BALANCE IN A MOUSE MODEL OF AUTISM: CORRELATION WITH BEHAVIORAL PHENOTYPES / M. Leonzino ; tutor: B. Chini ; coordinatore: A. E. Panerai. Università degli Studi di Milano, 2014 Jan 16. 26. ciclo, Anno Accademico 2013. [10.13130/leonzino-marianna_phd2014-01-16].

NEURONAL MORPHOLOGY AND EXCITATION/INHIBITION BALANCE IN A MOUSE MODEL OF AUTISM: CORRELATION WITH BEHAVIORAL PHENOTYPES

M. Leonzino
2014

Abstract

The role of oxytocin (OXT) in controlling social behavior suggests a link to neuropsychiatric conditions in which social behavior behavior is aberrant or even absent, such as autism. Mice lacking the OXT receptor (Oxtr-/-) display an autistic-like phenotype, including deficits in social interaction, impaired cognitive flexibility (murine correlates of autism core symptoms), increased aggression and susceptibility to seizure (common co-occurring conditions). The deficit in cognitive flexibility is particularly interesting, because it is present in few animal model of autism. For this reason we decided to investigate its underlying neurobiological and molecular mechanisms. First, we compared Oxtr+/+and Oxtr-/- neuronal morphology and spine remodeling following a cognitive behavioral test. Interestingly, we highlighted, in the Oxtr-/- mice, an enhanced connectivity and overuse of the dorsolateral striatum, possibly arising from an hippocampal dysfunction, and we proposed it as substrate for habit-like symptoms and cognitive rigidity. Second, we investigated, at the molecular level, possible sources of this hippocampal dysfunction. In particular, we analyzed Oxtr-/- hippocampal neurons for the expression of proteins involved in the setting and maintenance of excitatio-inhibition (E-I) balance. We found an upregulation of several inwardly-rectifying K+ channels (belonging to Kir2 and Kir3 families), which could alter membrane excitability, and a lack of the physiological upregulation of the chloride transporter KCC2 during development, that may lead to aberrant GABAergic signaling in mature neurons. These data give important indications that the E-I balance is altered at multiple levels in Oxtr-/- hippocampal neurons, as an altered ratio between Glutamatergic and GABAergic synapses was also previously observed in these cultures. These observations are particularly intriguing, because an E-I imbalance has been frequently associated with several neurodevelopmental disorders such as autism. Third, we disclosed an OXTR-mediated pathway modulating KCC2 expression that may restore a correct E-I balance in hippocampal neurons. All this information could be useful to understand the pathophysiology of cognitive rigidity and to develop new therapies addressing specific symptoms of autism.
16-gen-2014
Settore BIO/14 - Farmacologia
oxytocin ; autism ; KCC2 ; striatum ; hippocampus ; cognitive flexibility;
CHINI , BICE
PANERAI, ALBERTO EMILIO
Doctoral Thesis
NEURONAL MORPHOLOGY AND EXCITATION/INHIBITION BALANCE IN A MOUSE MODEL OF AUTISM: CORRELATION WITH BEHAVIORAL PHENOTYPES / M. Leonzino ; tutor: B. Chini ; coordinatore: A. E. Panerai. Università degli Studi di Milano, 2014 Jan 16. 26. ciclo, Anno Accademico 2013. [10.13130/leonzino-marianna_phd2014-01-16].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/229412
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