title: Intrahippocampal administration of the alpha-keto acids accumulating in maple syrup urine disease provokes learning deficits in rats.
abstract: Learning disability is a common feature of patients affected by maple syrup urine disease (MSUD). However, the pathomechanisms underlying learning deficit in this disorder are poorly known. In the present study, we investigated the effect of acute administration of the alpha-keto acids accumulating in MSUD into the hippocampus on the behavior of rats in the open field and in the inhibitory avoidance tasks. Adult male Wistar rats received intrahippocampal injections of alpha-ketoisocaproic acid (KIC, 8 micromol), alpha-ketoisovaleric acid (KIV, 5 micromol), alpha-keto-beta-methylvaleric acid (KMV, 5 micromol), or NaCl (8 micromol) (controls) immediately after or 10 min before training. Testing session was performed 24 h later. Posttraining administration of the keto acids had no effect on learning in the open-field task. In contrast, pretraining administration of KIV and KMV impaired habituation in the open field. Similarly, pretraining administration of KIC, KIV, and KMV affected rat performance in the inhibitory avoidance task, suggesting disruption of acquisition. The results indicate that the alpha-keto acids accumulating in MSUD induce learning deficits in aversive and nonaversive tasks. We therefore suggest that these findings may be related to the psychomotor delay/mental retardation observed in MSUD, and may indicate the contribution of increased brain concentrations of these organic acids to the pathophysiology of the neurological dysfunction of MSUD patients.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, CEP 90035-003, RS, Porto Alegre, Brazil.
authors.forename: Vilson
authors.initials: V
authors.lastname: de Castro Vasques
authors.forename: Melissa Avila
authors.initials: MA
authors.lastname: de Boer
authors.forename: Felipe
authors.initials: F
authors.lastname: Diligenti
authors.forename: Fabrício
authors.initials: F
authors.lastname: Brinco
authors.forename: Fabrício
authors.initials: F
authors.lastname: Mallmann
authors.forename: Carlos Fernando
authors.initials: CF
authors.lastname: Mello
authors.forename: Moacir
authors.initials: M
authors.lastname: Wajner
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D045782:Hemiterpenes; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007276:Injections, Intraventricular; D007651:Keto Acids / Q000008:administration & dosage*; D008297:Male; D008375:Maple Syrup Urine Disease / Q000378:metabolism* / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology
chemical_list: D045782:Hemiterpenes; D007651:Keto Acids; C016211:alpha-keto-beta-methylvaleric acid; C001505:alpha-ketoisovalerate; C013082:alpha-ketoisocaproic acid