Molecular and behavioral characterization of transgenic mice with impaired beta-neurexin-1 function as a mouse model of autism

Abstract

Synaptic circuitry in the brain is formed early during postnatal development and is continuously remodeled in the adult as a consequence of synaptic activity. Defects in synaptic function lie at the molecular basis of several disorders, including autism spectrum disorders (ASD). ASD are characterized by impairments in verbal and non-verbal communication and social interaction, and restricted and stereotyped patterns of behavior, interests and activities. The identification of mutations in neuroligin, neurexin and SHANK genes in patients with ASD has indicated a role of these proteins in autism. Neurexins are presynaptic partners of several postsynaptic proteins, including neuroligins. The characterization of the functional consequences of autism-associated mutations has led us to suggest a role for synaptic deficits of ß-neurexin-1 as a risk factor for autism (1). To analyze the impact of impaired ß-neurexin-1 function in ASD, we have generated a transgenic mouse line that expresses a mutant ß-neurexin-1 protein (HA-ßNrx1¿C) expected to function in a dominant-negative manner. In TRE-ßNrx1¿C mice, the expression of HA-ßNrx1¿C is controlled by the inducible TRE promoter. Here, we show inducible expression of HA-ßNrx1¿C in postnatal forebrain neurons of double transgenic TRE-HA-ßNrx1¿C; CAMKII¿tTA mice. In immunostaining experiments, HA-ßNrx1¿C is expressed in cortex and striatum. In cortical synaptosomes, HA-ßNrx1¿C is localized at presynaptic fractions, indicating incorporation of the mutant ß-neurexin-1 protein at presynaptic terminals in vivo. Moreover, we have evaluated the behavioral phenotype of TRE-HA-ßNrx1¿C; CamKII-tTA mice compared to control littermate mice and how they can be rescued by turning-off the transgene. The generation of a mouse model with inducible expression of a ß-neurexin-1 dominant negative mutant, such as the one described here, may help answering to what extent behavioral defects due to ß-neurexin-1 dysfunction can be rescued by recovering normal ß-neurexin-1 function. 1. Camacho-Garcia et al. Mutations affecting synaptic levels of neurexin-1ß in autism and mental retardation. Neurobiol. Dis.2012 Jul; 47 (1):135-43.