Interneuron-Specific Knockout of Semaphorin 3F Results in Increased Inflammation, Oxidative Stress and Autism-like Behavior.
The neuropathology of all neural circuits in ASD is dependent on changes in functional connectivity via the excitation/inhibition (E/I) ratio that impact routine neurotransmission, synaptic plasticity, and network function. We were the first to publish an extensive investigation of an animal model of autism and epilepsy (Barnes et al., 2009). The semaphorin/neuropilin gene family, an ASD associated set of genes, are guidance cues that control processes and cell motility in a wide variety of tissues. In the developing brain, these cues control interneuron migration/cell numbers, regulate neurite outgrowth (axon/dendrite), and control both GABA/excitatory synaptogenesis. Several groups, including our own, have noted behavioral phenotypes consistent with autism in both the semaphorin 3F (Sema 3F) and neuropilin 2 (NRP2) knockout mice. Similar to NRP2 KO mice, the interneuron specific but not excitatory neuron specific knockout of Sema 3F had decreased Parv+ and NPY+ interneurons and increased epileptogenesis with decreased social behaviors and increased repetitive behaviors compared to wild type littermates.
Objectives: We aimed to determine whether semaphorin 3F KO mice also presented with brain inflammation and oxidative stress that could be associated with ASD-like behavior.
Methods: DLX5/6 Cre Sema 3F Knockout mice and controls were tested for social novelty using the three chamber social interaction test. Markers of neuroinflammation (Iba1 for microiglia, and iNOS) and of oxidative stress (DHE for superoxide, 4-HNE for lipid peroxidation and 3-nitrotyrosine for protein nitrosylation) were assessed by immunostaining in three areas of DLX5/6 Cre Sema 3F Knockout mice and control brains.
Results: The significant increase in immunoreactivity of Iba1, a microglial marker, and of oxidative stress markers (DHE, 4HNE, iNOS, and 3-nitrotyrosine) in hippocampus, cortex and amygdala brain regions suggest increased inflammation and oxidation products within both the glia and neurons of the interneuron- specific Sema 3F KO mouse.
Conclusions: Thus, although this is a single ASD associated gene KO mouse, these data strongly suggest that genetic mouse models of autism with markers of inflammation will be an excellent tool to investigate the role of genomics, environmental factors influencing the immune system, clinical endophenotypes, and metabolic conditions. Most importantly, these models and others can define molecular mechanisms influencing the interactions among organ systems contributing to ASD brain dysfunction.