title: Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex.
abstract: Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia.
authors.affiliation: Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Pisansky
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wickham
authors.forename: Jianjun
authors.initials: J
authors.lastname: Su
authors.forename: Stephanie
authors.initials: S
authors.lastname: Fretham
authors.forename: Li-Lian
authors.initials: LL
authors.lastname: Yuan
authors.forename: Mu
authors.initials: M
authors.lastname: Sun
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Gewirtz
authors.forename: Michael K
authors.initials: MK
authors.lastname: Georgieff
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000097:blood / Q000150:complications / Q000503:physiopathology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D027682:Cation Transport Proteins / Q000235:genetics; D003677:Deficiency Diseases / Q000150:complications* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D048070:Fetal Nutrition Disorders / Q000097:blood / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007501:Iron / Q000378:metabolism; D000090463:Iron Deficiencies; D019189:Iron Metabolism Disorders / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood; D065808:Prepulse Inhibition / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000502:physiology*; D055366:Synaptic Potentials / Q000502:physiology; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D007501:Iron; D000099236:Solute Carrier Family 11, Member 2
keywords: dopamine; hippocampus; long-term potentiation; murine; schizophrenia