title: A sensitive period for GABAergic interneurons in the dentate gyrus in modulating sensorimotor gating.
abstract: Developmental perturbations during adolescence have been hypothesized to be a risk factor for the onset of several neuropsychiatric diseases. However the physiological alterations that result from such insults are incompletely understood. We investigated whether a defined perturbation during adolescence affected hippocampus-dependent sensorimotor gating functions, a proposed endophenotype in several psychiatric diseases, most notably schizophrenia. The developmental perturbation was induced during adolescence in mice using an antimitotic agent, methylazoxymethanol acetate (MAM), during postnatal weeks (PW) 4-6. MAM-treated mice showed a decrease in hippocampal neurogenesis immediately after treatment, which was restored by PW10 in adulthood. However, the mice treated with MAM during adolescent stages exhibited a persistent sensorimotor gating deficiency and a reduction in prepulse inhibition-related activation of hippocampal and prefrontal neurons in adulthood. Cellular analyses found a reduction of GABAergic inhibitory neurons and abnormal dendritic morphology of immature neurons in the dentate gyrus (DG). Interestingly, bilateral infusion of muscimol, a GABAA receptor agonist, into the DG region reversed the prepulse inhibition abnormality in MAM-treated mice. Furthermore, the behavioral deficits together with the decrease in the number of GABAergic neurons in this MAM model were rescued by exposure to an enriched environment during a defined critical adolescent period. These observations suggest a possible role for GABAergic interneurons in the DG during adolescence. This role may be related to the establishment of neural circuitry required for sensorimotor gating. It is plausible that changes in neurogenesis during this window may affect the survival of GABAergic interneurons, although this link needs to be causally addressed.
authors.affiliation: Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
authors.forename: Nannan
authors.initials: N
authors.lastname: Guo
authors.forename: Kaichi
authors.initials: K
authors.lastname: Yoshizaki
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kimura
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Suto
authors.forename: Yuchio
authors.initials: Y
authors.lastname: Yanagawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Osumi
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003423:Critical Period, Psychological; D003712:Dendrites; D018891:Dentate Gyrus / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089742:Doublecortin-Like Kinases; D004347:Drug Interactions; D004777:Environment; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D007266:Inhibition, Psychological; D007395:Interneurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008746:Methylazoxymethanol Acetate / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D055495:Neurogenesis / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D055139:Sensory Gating / Q000502:physiology*
chemical_list: D000089622:Doublecortin Domain Proteins; D018755:GABA Agonists; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D009118:Muscimol; D008746:Methylazoxymethanol Acetate; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases