RT Journal Article
SR Electronic
T1 Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2671
OP 2682
DO 10.1523/JNEUROSCI.2828-17.2018
VO 38
IS 11
A1 Michael S. Sidorov
A1 Matthew C. Judson
A1 Hyojin Kim
A1 Marie Rougie
A1 Alejandra I. Ferrer
A1 Viktoriya D. Nikolova
A1 Natallia V. Riddick
A1 Sheryl S. Moy
A1 Benjamin D. Philpot
YR 2018
UL http://www.jneurosci.org/content/38/11/2671.abstract
AB Angelman syndrome (AS), a neurodevelopmental disorder associated with intellectual disability, is caused by loss of maternal allele expression of UBE3A in neurons. Mouse models of AS faithfully recapitulate disease phenotypes across multiple domains, including behavior. Yet in AS, there has been only limited study of behaviors encoded by the prefrontal cortex, a region broadly involved in executive function and cognition. Because cognitive impairment is a core feature of AS, it is critical to develop behavioral readouts of prefrontal circuit function in AS mouse models. One such readout is behavioral extinction, which has been well described mechanistically and relies upon prefrontal circuits in rodents. Here we report exaggerated operant extinction in male AS model mice, concomitant with enhanced excitability in medial prefrontal neurons from male and female AS model mice. Abnormal behavior was specific to operant extinction, as two other prefrontally dependent tasks (cued fear extinction and visuospatial discrimination) were largely normal in AS model mice. Inducible deletion of Ube3a during adulthood was not sufficient to drive abnormal extinction, supporting the hypothesis that there is an early critical period for development of cognitive phenotypes in AS. This work represents the first formal experimental analysis of prefrontal circuit function in AS, and identifies operant extinction as a useful experimental paradigm for modeling cognitive aspects of AS in mice.SIGNIFICANCE STATEMENT Prefrontal cortex encodes “high-level” cognitive processes. Thus, understanding prefrontal function is critical in neurodevelopmental disorders where cognitive impairment is highly penetrant. Angelman syndrome is a neurodevelopmental disorder associated with speech and motor impairments, an outwardly happy demeanor, and intellectual disability. We describe a behavioral phenotype in a mouse model of Angelman syndrome and related abnormalities in prefrontal cortex function. We hypothesize that robust and reliable prefrontally encoded behavior may be used to model cognitive impairments in Angelman syndrome.