Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications.
The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.
Bilsland
James G
JG
Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme, The Neuroscience Research Centre, Essex, UK.
Wheeldon
Alan
A
Mead
Andrew
A
Znamenskiy
Petr
P
Almond
Sarah
S
Waters
Kerry A
KA
Thakur
Matthew
M
Beaumont
Vahri
V
Bonnert
Timothy P
TP
Heavens
Robert
R
Whiting
Paul
P
McAllister
George
G
Munoz-Sanjuan
Ignacio
I
D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology*; D001973:Bromodeoxyuridine; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003863:Depression / Q000235:genetics / Q000523:psychology; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D019417:Hindlimb Suspension; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases; D021641:Recognition, Psychology / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology
D012701:Serotonin; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D001973:Bromodeoxyuridine; D013936:Thymidine; D004298:Dopamine