Comprehensive Behavioral Phenotyping of BDNF-Overexpressing Transgenic Mice

Background:

Brain-derived neurotrophic factor (BDNF) is a signaling molecule involved in brain development, including aspects of neuronal differentiation, synapse formation, dendritic spine morphology, and axonal growth. BDNF has been implicated as a target in numerous neurological diseases. Autism is a neurodevelopmental disorder believed to have a strong genetic component. It is characterized by aberrant reciprocal social interactions, impaired communication, and repetitive behaviors. Unusual levels of BDNF have been reported in several autism studies, particularly during early development.

Objectives:

In order to better understand the role of BDNF in autism, we are conducting comprehensive behavioral phenotyping on a line of the BDNF-overexpressing mice as well as correlative BDNF protein expression analysis.

Methods:
Mice with the BDNF transgene expressed on a forebrain CaMKII promoter (Huang et al., 1999) were purchased from JAX (Bar Harbor, ME). Comprehensive behavioral testing of general health, reflexes, motor activity, social behavior, anxiety-like behavior, and learning and memory abilities was conducted on BDNF-overexpressing mice and their wildtype littermates as routinely conducted in our laboratory and previously described (Bailey et al, 2007; Chadman et al., 2008). Juvenile play was recorded at day 21, prior to weaning. All other behavioral tests were conducted on animals age 6-8 weeks.

Results:

Data indicate that BDNF-overexpressing mice are similar to their wildtype littermates on standardized measures of general health, neurological reflexes, motor activity, and social behavior. However, there were subtle differences in anxiety-like behaviors between BDNF-overexpressing mice and their littermates. Additionally, deficits in the cued component of cued and contextual fear conditioning in the BDNF-overexpressing mice were observed which may indicate a mild learning impairment. Currently, we are assessing performance on the Morris water maze spatial learning task, and conducting BDNF protein expression analysis for correlations with behavioral scores.

Conclusions:

Behavioral phenotyping has revealed only minor differences between BDNF-overexpressing transgenic mice and their wildtype littermates, suggesting that overexpression of BDNF does not significantly impact general health, neurological reflexes, motor abilities, juvenile reciprocal social interactions, or adult social approach in mice. However, forebrain BDNF-overexpression may influence anxiety-like behaviors and learning. In connection with this, previous work reported that αCaMKII overexpression impaired retrieval of object recognition and fear-related memory (Cao et al., 2008). Further studies in progress will investigate the hypothesis that excess forebrain BDNF affects synaptic plasticity relevant to cognitive functions, including social cognition.