Neuroglia, cells of the CNS derived from the neuroectoderm ( astroglia and oligodendroglia) and mesoderm (microglia) contribute to the establishment of neuronal networks and brain connectivity. Recent studies have shown the important role of neuroglia and neuroimmune pathways in synaptic function and neuronal homeostasis. Disturbances of neuroglia cells and their activation patterns facilitate the activation of cytokines, chemokines and signaling pathways such as Toll-like receptors (TLRs), activation that may influence neuronal and synaptic function.
Objectives:
Our lab has focused on studies of cytokines/chemokine networks as well as TLRs signaling pathways in the cerebral cortex of brains from children with autism and controls.
Methods:
Proteomic and multiplexed techniques as well as quantitative PCR studies were used to identify the profiles of cytokines, chemokines and TLR pathways in different cortical regions in brain obtained from patients with autism and controls.
Results:
Patterns of neuroglial activation and expression of signaling pathways associated with innate immunity are differentially expressed in the cerebral cortex. Cytokines such as IL-6 and TGF-1 beta as well as the chemokine CCL2 (MCP-1) are prominently overexpressed in selected areas of the cortex such as the anterior cingulated gyrus (ACG) and frontal cortex (FC). Signaling pathways associated with innate immunity such as TLRs, appear also to be selectively expressed across cortical areas. TLR2 and other downstream signaling genes are particularly up-regulated in the ACG as compared with other cortical regions. Interestingly, the ACG appears to be the cortical area with most selective increases of innate neuroimmunity. This selective expression is associated with the magnitude of neuroglia activation and may associated with patterns of neuronal susceptibility and cortical dysfunction.
Conclusions:
Selective expression of cytokines, chemokines and TLRs were observed in cortical brain regions. The ACG appears to be one of the most prominent cortical brain regions with most activation of innate neuroimmunity. The patterns of expression appears to be associated with the magnitude of astroglia and microglia activation and demonstrate the involvement of innate neuro immunity in pathogenic mechanisms in autism.
(Pardo’s Lab is supported by The Bart McLean Fund for Neuroimmunology Research & The Peter Emch Fund for Autism Research. Previous support from Cure Autism Now/Autism Speaks, The Autism Tissue Project and The University of Maryland Brain Bank Developmental Disorders is also acknowledged.)