Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice.
Npas3 is a member of the bHLH-PAS superfamily of transcription factors that is expressed broadly in the developing neuroepithelium. To study the function of this gene, mice deficient in Npas3 were generated and characterized. Npas3-/- mice were growth-retarded and exhibited developmental brain abnormalities that included a reduction in size of the anterior hippocampus, hypoplasia of the corpus callosum and enlargement of the ventricles. A number of behavioural abnormalities were identified in Npas3-/- mice including locomotor hyperactivity, subtle gait defects, impairment of prepulse inhibition of acoustic startle, deficit in recognition memory and altered anxiety-related responses. Characterization of neurosignaling pathways using several pharmacological agents revealed dysfunctional glutamate, dopamine and serotonin neurotransmitter signaling. Consistent with these findings, we identified a significant alteration in cortical PSD-95 expression, a PDZ-containing protein that has been shown to be involved in postsynaptic signal transduction. Together, our observations indicate an important role for Npas3 in controlling normal brain development and neurosignaling pathways.
Brunskill
Eric W
EW
Division of Cardiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. eric.brunskill@uc.edu
Ehrman
Lisa A
LA
Williams
Michael T
MT
Klanke
Justin
J
Hammer
Daniel
D
Schaefer
Tori L
TL
Sah
Renu
R
Dorn
Gerald W
GW
Potter
S Steven
SS
Vorhees
Charles V
CV
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000002:abnormalities; D000076122:Disks Large Homolog 4 Protein; D020234:Gait Ataxia / Q000235:genetics / Q000503:physiopathology; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009420:Nervous System / Q000254:growth & development*; D018377:Neurotransmitter Agents / Q000378:metabolism; D004856:Postural Balance / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; C501447:Dlg4 protein, mouse; C492587:Npas3 protein, mouse