Open AccessEGF Treatment Improves Motor Behavior and Cortical GABAergic Function in the R6/2 Mouse Model of Huntington’s Disease
Author(s) -
Felecia M. Marottoli,
Mercedes Priego,
Edén Flores-Barrera,
Rohan Pisharody,
Steve Zaldua,
Kelly Fan,
Giri K. Ekkurthi,
Scott T. Brady,
Gerardo Morfini,
Kuei Y. Tseng,
Leon M. Tai
Publication year - 2019
Publication title -
molecular neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.569
H-Index - 111
eISSN - 1559-1182
pISSN - 0893-7648
DOI - 10.1007/s12035-019-1634-y
Subject(s) - huntingtin , gabaergic , neuroscience , huntington's disease , epidermal growth factor , neurology , huntingtin protein , biology , psychology , disease , medicine , receptor , inhibitory postsynaptic potential
Recent evidence indicates that disruption of epidermal growth factor (EGF) signaling by mutant huntingtin (polyQ-htt) may contribute to the onset of behavioral deficits observed in Huntington's disease (HD) through a variety of mechanisms, including cerebrovascular dysfunction. Yet, whether EGF signaling modulates the development of HD pathology and the associated behavioral impairments remain unclear. To gain insight on this issue, we used the R6/2 mouse model of HD to assess the impact of chronic EGF treatment on behavior, and cerebrovascular and cortical neuronal functions. We found that bi-weekly treatment with a low dose of EGF (300 µg/kg, i.p.) for 6 weeks was sufficient to effectively improve motor behavior in R6/2 mice and diminish mortality, compared to vehicle-treated littermates. These beneficial effects of EGF treatment were dissociated from changes in cerebrovascular leakiness, a result that was surprising given that EGF ameliorates this deficit in other neurodegenerative diseases. Rather, the beneficial effect of EGF on R6/2 mice behavior was concomitant with a marked amelioration of cortical GABAergic function. As GABAergic transmission in cortical circuits is disrupted in HD, these novel data suggest a potential mechanistic link between deficits in EGF signaling and GABAergic dysfunction in the progression of HD.