Activity-Dependent Changes in Microtubule-Dependent Synaptic Transport in an Animal Model of Autism

Background:  Activity-dependent changes in the brain include various processes at the synapse, cell body and nucleus as well as an increase in their communications, which is mostly served by cytoskeletal structures, microtubules and actin filaments. Contrary to the previous view that microtubules are stable in mature neurons, we find that microtubules change their stability following behavioral activity. We also find that a microtubule inhibitor, stathmin, controls these changes in microtubule stability in response to activity. 

Objectives:  We tested the hypothesis that activity-dependent changes in dentate gyrus microtubules may lead to changes in synaptic transport that lead to ASD-related behavioral phenotype.

Methods:   We have generated Stat4A mutant mice where stathmin expression is controlled by tetracycline-dependent tTA system. In the hippocampus, Stat4A mice have strong expression in the dentate gyrus. We will test these mice in several social and cognition behaviors related to ASD.

Results:  Stat4A mice show deficits in affiliative behaviors (maternal pup retrieval), anxiety and motivation. There is increasing evidence suggesting that autism and maternal depression and deprivation are linked. More specifically, the environment, both prenatally and during early postnatal life is a significant factor in the development of psychiatric disorders, including autism, in offspring (Gilbert et al., 2009; Green et al., 2010; Feldman, 2012; Oh et al., 2013). The Jan and Jan group has shown that pups’ interactions with their mother strongly influence the pup's vocal communication, ultrasonic vocalizations (USV) (Young et al. 2010). We will next test USV in pups born and raised by Stat4A mothers as deficits in USV have been found to be indicative of behaviors similar to ASD in humans. If we find these changes it will be consistent with social communication deficits in autism.

Conclusions: Our current results suggest that dentate gyrus microtubules controlled by stathmin are involved in behaviors related to ASD. Therefore, Stat4A mouse may be a useful animal model for ASD.