Developmental Expression of Neuroligin and Neurexin mRNAs in the Fragile X Mouse

Background: Fragile X Syndrome is one of the most well known genetic causes of autism or autism-related behaviours. Up to 25% of Fragile X patients are diagnosed with autism and 2% to 6% of autism patients have Fragile X. This neurodevelopmental disorder is caused by silencing of the FMR1 gene, located on the X chromosome, that leads to dysregulation of mRNA translation. Recent research has focused attention on synapse structure and function as a primary contributor to the development of fragile X and autism spectrum disorders. Neuroligins (NLGNs) and neurexins (NRXNs) are trans-synaptic cell adhesion molecules that are important for synapse maturation. We have previously examined neuroligin expression in the adult fmr1-/- mouse, the mouse model of Fragile X Syndrome. Our data showed male-specific increase of NLGN1 mRNA in the fmr1-/- somatosensory cortex (S1) and hippocampus (HIP). Changes in the timing and level of expression of these synaptic genes during postnatal development may influence the establishment of a balanced neural circuit and affect the architecture of the brain network.

Objectives: The objective of this study is to examine the developmental expression profile of neuroligin and neurexin mRNA in the fmr1-/- mouse.

Methods: Our target genes include known mouse genes NLGN1, 2, 3, and 4 and NRXN1, 2 and 3. In situ hybridization is employed to examine temporal and spatial patterns of these target genes during postnatal development in wildtype (FVB.129P2(B6)) and fmr1-/- (FVB.129P2(B6)-Fmr1tm1Cgr) mice.  

Results: NLGN1 – Patterns of expression for NLGN1 were similar in WT and fmr1-/- mice.  Expression levels were highest at postnatal day (P) 7 in both the HIP and S1 and decreased over time. NLGN2 – WT mice showed increasing expression of NLGN2 mRNA over the first 3 weeks, with peak expression at P21, followed by a decrease over the next 2 weeks.  Fmr1-/- mice showed altered expression of NLGN2 mRNA in the CA1 region of the hippocampus, while remaining brain regions were similar to WT patterns. NLGN3 – NLGN3 mRNA expression increased in WT mice over the first 2 weeks and then was reduced across brain regions by P21. Interestingly, sexual dimorphic expression of NLGN3 mRNA was observed in dentate gyrus in WT mice.  In addition, altered expression patterns at P14 and P21 were present in both male and female fmr1-/- mice.

Conclusions: Transient changes in neuroligin gene expression are observed during the window of synaptic maturation in fmr1-/- mice. Ongoing analysis will extend this work to include neuroligin 4 and the neurexin mRNAs. This research will further our understanding of the shared neurobiology between autism and Fragile X Syndrome.