Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Apr;21(4):e12797.
doi: 10.1111/gbb.12797. Epub 2022 Jan 25.

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

Sophie Waldron  1 , Rachel Pass  2   3 , Simonas Griesius  4 , Jack R Mellor  4 , Emma S J Robinson  4 , Kerrie L Thomas  2 , Lawrence S Wilkinson  1   2 , Trevor Humby  1 , Jeremy Hall  2   5 , Dominic M Dwyer  1
Affiliations

Behavioural and molecular characterisation of the Dlg2 haploinsufficiency rat model of genetic risk for psychiatric disorder

Sophie Waldron et al. Genes Brain Behav. 2022 Apr.

Abstract

Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2+/- rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2+/- rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2+/- mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.

Keywords: DLG2; PCP locomotion; animal models; autism spectrum disorder; schizophrenia; sensorimotor gating; synaptic plasticity.

PubMed Disclaimer

Conflict of interest statement

The authors confirm there are no conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
mRNA expression of Dlg1‐4 in Dlg2 +/− and wild‐type rats. Data is shown as mean ± SEM fold change plotted plus individual data points for Dlg2 PFC (A), Dlg2 hippocampus (B), Dlg1 PFC (C), Dlg1 hippocampus (D), Dlg3 PFC (E), Dlg3 hippocampus (F), Dlg4 PFC (G) and Dlg4 hippocampus (H). n = 8 wild‐type, 8 Dlg2 +/− . The Dlg2 +/− rat shows a reduction of Dlg2 expression in the hippocampus and prefrontal cortex compared to wild‐types, with no changes in the expression of Dlg1, Dlg3 or Dlg4
FIGURE 2
FIGURE 2
Expression of proteins PSD‐93 (A), PSD‐95 (B) and NR1 NMDA receptor subunit (C) in Dlg2 +/− and wild‐type rats. These were assessed across four brain regions: prefrontal cortex (PFC), posterior cortex (CX), hippocampus (HP) and cerebellum (CB). Cerebellar NR1 expression was too low for analysis thus is not reported. Data is shown as mean ± SEM integrated density plotted plus individual data points. n = 12 wild‐type, 12 Dlg2 +/− . Across the prefrontal cortex, posterior cortex, hippocampus and cerebellum Dlg2 +/− rats showed a decrease in PSD‐93 compared to wild‐types, with no changes in PSD‐95 or NR1 NMDA receptor subunit levels
FIGURE 3
FIGURE 3
Effect of Dlg2 heterozygous knockout on anxiety‐related behaviour in the elevated plus maze. Data is shown as mean ± SEM with data points representing individuals (A) time in zone (B) head dips (C) stretch‐attend postures (D) grooming (E) defecation (F) distance moved (G) velocity. n = 24 wild‐type, 21 Dlg2 +/− . Dlg2 +/− rats performed comparably to wild‐types on elevated plus maze measures of anxiety and hyperactivity
FIGURE 4
FIGURE 4
Effect of Dlg2 heterozygous knockout on open‐field measures Data is shown as mean ± SEM plus individual values for (A) time in zone (B) velocity (C) distance travelled and (D) defection. n = 24 wild‐type, 21 Dlg2 +/− . Dlg2 +/− rats performed comparably to wild‐types on open‐field measures of anxiety and hyperactivity
FIGURE 5
FIGURE 5
Effect of Dlg2 heterozygosity on acoustic startle response and pre‐pulse inhibition. (A) Mean ± SEM weight‐adjusted ASR to 70–120 dB pulses above background. (B) Mean ± SEM habituation of startle response through increasing pulse trials and (C) Mean ± SEM PPI plus individual values with 4, 8 and 16 dB (above background) pre‐pulse. n = 24 wild‐type, 21 Dlg2 +/− . Dlg2 +/− rats did not differ from wild‐types in their startle response, habituation of startle responding over trials or pre‐pulse inhibition
FIGURE 6
FIGURE 6
The drinking behaviour of Dlg2 +/− and wild‐type rats when presented with low and high concentrations of sucrose. Data is shown as mean ± SEM plus individual values (A) consumption (g) and (B) lick cluster size. n = 28 wild‐type, 20 Dlg2 +/− . Consumption and lick cluster size to low and high sucrose solutions did not vary with genotype
FIGURE 7
FIGURE 7
Dlg2 +/− and wild‐type exploration times on the social preference task. Data is shown as mean ± SEM plus individual values (A) raw exploration and (B) d2 discrimination ratios. n = 26 wild‐type, 32 Dlg2 +/− . There was no effect of genotype on rodents preference for exploring the unknown conspecific relative to the object in the social preference task
FIGURE 8
FIGURE 8
Locomotor activity in response to PCP injection in Dlg2 +/− and wild‐type rats. Data is shown as mean ± SEM distance travelled plotted in 10‐min bins. The dotted line just past 30 min denotes when the PCP injection occurred. n = 26 wild‐type, 32 Dlg2 +/− . Dlg2 +/− rats demonstrated a locomotor response to PCP which was more sustained and exaggerated than wild‐types
See this image and copyright information in PMC

References

    1. Ruzzo EK, Pérez‐Cano L, Jung JY, et al. Inherited and De Novo genetic risk for autism impacts shared networks. Cell. 2019;178(4):850‐866.e26. doi:10.1016/j.cell.2019.07.015 - DOI - PMC - PubMed
    1. Reggiani C, Coppens S, Sekhara T, et al. Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability. Genome med. 2017;9(1):1‐20. doi:10.1186/s13073-017-0452-y - DOI - PMC - PubMed
    1. Kirov G, Pocklington AJ, Holmans P, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17(2):142‐153. doi:10.1038/mp.2011.154 - DOI - PMC - PubMed
    1. Egger G, Roetzer KM, Noor A, et al. Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families. Neurogenetics. 2014;15:117‐127. doi:10.1007/s10048-014-0394-0 - DOI - PubMed
    1. Noor A, Lionel AC, Cohen‐Woods S, et al. Copy number variant study of bipolar disorder in Canadian and UKpopulations implicates synaptic genes. Am J med Genet Part B Neuropsychiatr Genet. 2014;165(4):303‐313. doi:10.1002/ajmg.b.32232 - DOI - PubMed

Publication types