title: Delayed in vitro development of Up states but normal network plasticity in Fragile X circuits.
abstract: A broad range of neurophysiological phenotypes have been reported since the generation of the first mouse model of Fragile X syndrome (FXS). However, it remains unclear which phenotypes are causally related to the cognitive deficits associated with FXS. Indeed, because many of these phenotypes are known to be modulated by experience, a confounding factor in the interpretation of many studies is whether some phenotypes are an indirect consequence of abnormal development and experience. To help diminish this confound we first conducted an in vitro developmental study of spontaneous neural dynamics in cortical organotypic cultures. A significant developmental increase in network activity and Up states was observed in both wild-type and Fmr1(-/y) circuits, along with a specific developmental delay in the emergence of Up states in knockout circuits. To determine whether Up state regulation is generally impaired in FXS circuits, we examined Up state plasticity using chronic optogenetic stimulation. Wild-type and Fmr1(-/y) stimulated circuits exhibited a significant decrease in overall spontaneous activity including Up state frequency; however, no significant effect of genotype was observed. These results demonstrate that developmental delays characteristic of FXS are recapitulated during in vitro development, and that Up state abnormalities are probably a direct consequence of the disease, and not an indirect consequence of abnormal experience. However, the fact that Fmr1(-/y) circuits exhibited normal homeostatic modulation of Up states suggests that these plasticity mechanisms are largely intact, and that some of the previously reported plasticity deficits could reflect abnormal experience or the engagement of compensatory mechanisms.
authors.affiliation: Departments of Neurobiology and Psychology, Integrative Center for Learning and Memory, University of California, 695 Young Drive, Gonda, Los Angeles, CA, 90095, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Motanis
authors.affiliation: Departments of Neurobiology and Psychology, Integrative Center for Learning and Memory, University of California, 695 Young Drive, Gonda, Los Angeles, CA, 90095, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Buonomano
mesh_terms: D000818:Animals; D058256:Brain Waves; D002540:Cerebral Cortex / Q000503:physiopathology*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D005600:Fragile X Syndrome / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000503:physiopathology; D009473:Neuronal Plasticity; D009474:Neurons / Q000502:physiology*; D062308:Optogenetics
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse
keywords: homeostatic plasticity; mouse; optogenetic stimulation; organotypic slices; spontaneous activity