NMDA receptor‐deficient mice display sexual dimorphism in the onset and severity of behavioural abnormalities

Abstract

N-methyl-D-aspartate (NMDA) receptor-deficient mice can be used to understand the role that NMDA receptors (NMDARs) play in the pathophysiology of neurodevelopmental disorders such as schizophrenia. Genetically modified mice with low levels of NR1 subunit (NR1 knockdown mice) have reduced receptor levels throughout development, and have robust abnormalities in behaviours that are relevant to schizophrenia. We traced the onset and severity of these behaviours at three developmental stages to understand when in development the underlying circuits depend on intact NMDAR function. We examined social behaviour, working memory, executive function, locomotor activity and stereotypy at 3, 6 and 12 weeks of age in NR1 knockdown mice and their wild-type littermates. We discovered that each of these behaviours had a unique developmental trajectory in mutant mice, and males showed an earlier onset and severity than females in several behaviours. Hyperlocomotion was most substantial in juvenile mice and plateaued in adult mice, whereas stereotypy progressively worsened with age. Impairments in working memory and sociability were sexually dimorphic, with deficits first detected in peri-adolescent males but only detected in adult females. Interestingly, executive function was most impaired in peri-adolescent mice of either sex. Furthermore, while juvenile mutant mice had some ability to problem solve in the puzzle box test, the same mice lost this ability when tested 4 weeks later. Our studies highlight key developmental periods for males and females in the expression of behaviours that are relevant to psychiatric disorders.

Heterozygous deletion of the LRFN2 gene is associated with working memory deficits

“…We argue that heterozygous LRFN2 deletion likely contributes to the learning disability seen in the family members because: (i) LRFN2 co-localizes with NR1 in the postsynaptic region; and (ii) dysfunction of NMDARs have been shown to alter excitatory synapse functioning and WM processes. [27][28][29] To date, two cases with deletions encompassing LRFN2 are available in public databases (ClinGen or Decipher (295383)). Their deletions were larger than that reported here (respectively, 7.87 and 3.19 Mb) and included numerous genes in the vicinity of LRFN2.…”

“…Expression levels of the NR1 subunit, as well as the presence of functional NMDARs, have been shown to be critical for glutamate signaling and WM. [27][28][29] Dystrobrevin binding protein-1 (dysbindin or DTNBP1) null mice display deficits in WM performance, secondary to NR1 dysfunction. 27 Knockdown of NR1 expression in mice 28 and blockade of NMDARs in patients 29 also cause WM deficits.…”

Effects of β-Arrestin-Biased Dopamine D2 Receptor Ligands on Schizophrenia-Like Behavior in Hypoglutamatergic Mice

“…These mutants are hyperactive in the open field, deficient in prepulse inhibition (PPI), display abnormal social and sexual behaviors, and are impaired in cognitive performance (Mohn et al, 1999;Duncan et al, 2004Duncan et al, , 2006aHalene et al, 2009;Milenkovic et al, 2014). Haloperidol, clozapine, and olanzapine reduce their hyperactivity and improve PPI, whereas clozapine partially restores their sexual behavior.…”

Lamotrigine Reduces Inflammatory Response and Ameliorates Executive Function Deterioration in an Alzheimer’s-Like Mouse Model

“…A puzzle box assay, adapted from Milenkovic et al [18], was used to assess mouse executive function. The apparatus is a Plexiglas white box, divided by a removable barrier into a goal box (goal zone, 15 × 28 cm) and a larger start box (start zone, 58 × 28 cm) with an underpass that allows animals to move between the two compartments.…”