TY - JOUR
T1 - Neurodevelopmental and cognitive behavior of glutaryl-CoA dehydrogenase deficient knockout mice
AU - Busanello, Estela Natacha Brandt
AU - Pettenuzzo, Letícia
AU - Botton, Paulo Henrique
AU - Pandolfo, Pablo
AU - De Souza, Diogo Onofre Gomes
AU - Woontner, Michael
AU - Goodman, Stephen
AU - Koeller, David
AU - Wajner, Moacir
N1 - Funding Information:
We are grateful to the financial support of CNPq , PROPESq/UFRGS , FAPERGS , PRONEX , FINEP Rede Instituto Brasileiro de Neurociência (IBN-Net) #01.06.0842-00 , and Instituto Nacional de Ciência e Tecnologia-Excitotoxicidade e Neuroproteção (INCT-EN) .
PY - 2013/2/7
Y1 - 2013/2/7
N2 - Aims: The establishment of a genetic knockout murine model of glutaric acidemia type I (GAI) with complete loss of glutaryl-CoA dehydrogenase (GCDH) activity has been used to investigate the pathological mechanisms underlying neurological symptoms in this disorder. However, very little has been reported on the neurobehavior of GCDH deficient mice (Gcdh-/-). Main methods: In the present study we evaluated physical (body and weight gain) and neuromotor development (appearance of coat, upper incisor eruption, eye-opening day, motor coordination, muscular strength and climbing), as well as cognitive behavior (inhibitory avoidance) in Gcdh-/-, as compared to wild type (WT) mice. Key findings: We found that Gcdh-/- mice did not differ in body and weight gain, appearance of coat, upper incisor eruption, motor coordination and muscular strength, but had a significant delayed eye opening, implying a mild impairment of neurodevelopment in these animals. Furthermore, the climbing behavior was significantly higher in Gcdh-/- as compared to WT mice, suggesting an altered dopaminergic function. Finally, Gcdh-/- mice presented a deficit of short- and long-term memories in the inhibitory avoidance task. Significance: Although it is difficult to extrapolate the present findings to the human condition, our present data are particularly interesting in view of the psychomotor/mental delay that occurs in a significant number of GAI patients with no previous history of acute encephalopathy with striatum destruction. Strict and early treatment possibly associated with novel therapies seems therefore important to prevent learning/memory disabilities in GAI patients.
AB - Aims: The establishment of a genetic knockout murine model of glutaric acidemia type I (GAI) with complete loss of glutaryl-CoA dehydrogenase (GCDH) activity has been used to investigate the pathological mechanisms underlying neurological symptoms in this disorder. However, very little has been reported on the neurobehavior of GCDH deficient mice (Gcdh-/-). Main methods: In the present study we evaluated physical (body and weight gain) and neuromotor development (appearance of coat, upper incisor eruption, eye-opening day, motor coordination, muscular strength and climbing), as well as cognitive behavior (inhibitory avoidance) in Gcdh-/-, as compared to wild type (WT) mice. Key findings: We found that Gcdh-/- mice did not differ in body and weight gain, appearance of coat, upper incisor eruption, motor coordination and muscular strength, but had a significant delayed eye opening, implying a mild impairment of neurodevelopment in these animals. Furthermore, the climbing behavior was significantly higher in Gcdh-/- as compared to WT mice, suggesting an altered dopaminergic function. Finally, Gcdh-/- mice presented a deficit of short- and long-term memories in the inhibitory avoidance task. Significance: Although it is difficult to extrapolate the present findings to the human condition, our present data are particularly interesting in view of the psychomotor/mental delay that occurs in a significant number of GAI patients with no previous history of acute encephalopathy with striatum destruction. Strict and early treatment possibly associated with novel therapies seems therefore important to prevent learning/memory disabilities in GAI patients.
KW - Climbing behavior
KW - Cognitive behavior
KW - Glutaric acidemia type I
KW - Knockout mice model
KW - Mice behavior
KW - Neurodevelopment
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U2 - 10.1016/j.lfs.2012.11.013
DO - 10.1016/j.lfs.2012.11.013
M3 - Article
C2 - 23201428
AN - SCOPUS:84872282404
SN - 0024-3205
VL - 92
SP - 137
EP - 142
JO - Life Sciences
JF - Life Sciences
IS - 2
ER -