Schizophrenia-related endophenotypes in heterozygous neuregulin-1 'knockout' mice.
Neuregulin-1 (NRG1) has been shown to play a role in glutamatergic neurotransmission and is a risk gene for schizophrenia, in which there is evidence for hypoglutamatergic function. Sensitivity to the behavioural effects of the psychotomimetic N-methyl-D-aspartate receptor antagonists MK-801 and phencyclidine (PCP) was examined in mutant mice with heterozygous deletion of NRG1. Social behaviour (sociability, social novelty preference and dyadic interaction), together with exploratory activity, was assessed following acute or subchronic administration of MK-801 (0.1 and 0.2 mg/kg) or PCP (5 mg/kg). In untreated NRG1 mutants, levels of glutamate, N-acetylaspartate and GABA were determined using high-performance liquid chromatography and regional brain volumes were assessed using magnetic resonance imaging at 7T. NRG1 mutants, particularly males, displayed decreased responsivity to the locomotor-activating effects of acute PCP. Subchronic MK-801 and PCP disrupted sociability and social novelty preference in mutants and wildtypes and reversed the increase in both exploratory activity and social dominance-related behaviours observed in vehicle-treated mutants. No phenotypic differences were demonstrated in N-acetylaspartate, glutamate or GABA levels. The total ventricular and olfactory bulb volume was decreased in mutants. These data indicate a subtle role for NRG1 in modulating several schizophrenia-relevant processes including the effects of psychotomimetic N-methyl-D-aspartate receptor antagonists.
O'Tuathaigh
C M P
CM
Molecular & Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. cotuathaigh@rcsi.ie
Harte
M
M
O'Leary
C
C
O'Sullivan
G J
GJ
Blau
C
C
Lai
D
D
Harvey
R P
RP
Tighe
O
O
Fagan
A J
AJ
Kerskens
C
C
Reynolds
G P
GP
Waddington
J L
JL
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000032:analysis; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D010622:Phencyclidine / Q000494:pharmacology; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000503:physiopathology*; D012737:Sex Factors; D012919:Social Behavior; D005680:gamma-Aminobutyric Acid / Q000032:analysis
D018691:Excitatory Amino Acid Antagonists; D020890:Neuregulin-1; D016194:Receptors, N-Methyl-D-Aspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016291:Dizocilpine Maleate; C000179:N-acetylaspartate; D010622:Phencyclidine