The Association of ASD-like Behavior, Inflammatory Signaling, and Oxidative Stress Cascades in Semaphorin 3F KO Mice

Background:  The neuropathology of all neural circuits in ASD are dependent on changes in functional connectivity via the excitation/inhibition (E/I) ratio. The changes in E/I ratio 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 including the CNS, heart, lung, kidney, and immune system. In the developing brain, these cues control interneuron migration/cell numbers, regulate neurite outgrowth (axon/dendrite), and control both GABA/excitatory synaptogenesis.

Objectives: The objective was to define the associations between inflammation, oxidative stress, and ASD-like behaviors.

Methods:  Several groups, including our own, have noted behavioral phenotypes consistent with autism in both the semaphorin 3F and neuropilin 2 (NRP2) knockout mice. Since we observed decreased cell numbers of fast spiking Parv+ interneurons in NRP2 KO mice, we created cell specific knockouts of the ligand Semaphorin 3F (Sema 3F). The interneuron cell numbers, behaviors, inflammatory cascades, and oxidative stress signaling were investigated in these mice.

Results: Similar to NRP2 KO mice, the interneuron specific but not excitatory neuron specific knockout of Sema 3F had decreases in Parv+ and NPY+ interneuron and increased epileptogenesis. As a group, these animals had decreased social behaviors and increased repetitive behaviors compared to wild type littermates. The Sema 3F-NRP2 system signals through the NADPH oxidase MICAL1/2/3 to control the rac/rho mediated growth cone collapse via CRMP2. Interestingly, Judy Atwater and colleagues at the UC Davis MIND institute detected an auto-antibody against CRMP2 among the maternal inflammatory response which correlated with an ASD diagnosis. The staining for oxidative stress markers (4HNE, DHE), iNOS, and 3-nitrotyrosine (markers of inflammation) suggest increased products both within the glia and neurons of the interneuron specific Sema 3F conditional KO mouse. At least one marker of microglial activation Iba1 is increased in these same mice.

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 (metals, obesity), 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.