Expression profiles of the autism-related SHANK proteins in the human brain

Abstract

Background SHANKs are major scaffolding proteins at postsynaptic densities (PSDs) in the central nervous system. Mutations in all three family members have been associated with neurodevelopmental disorders such as autism spectrum disorders (ASDs). Despite the pathophysiological importance of SHANK2 and SHANK3 mutations in humans, research on the expression of these proteins is mostly based on rodent model organisms. Results In the present study, cellular and neuropil SHANK2 expression was analyzed by immunofluorescence (IF) staining of post mortem human brain tissue from four male individuals (19 brain regions). Mouse brains were analyzed in comparison to evaluate the degree of phylogenetic conservation. Furthermore, SHANK2 and SHANK3 isoform patterns were compared in human and mouse brain lysates. While isoform expression and subcellular distribution were largely conserved, differences in neuropil levels of SHANK2 were found by IF staining: Maximum expression was concordantly measured in the cerebellum; however, higher SHANK2 expression was detected in the human brainstem and thalamus when compared to mice. One of the lowest SHANK2 levels was found in the human amygdala, a moderately expressing region in mouse. Quantification of SHANK3 IF in mouse brains unveiled a distribution comparable to humans. Conclusions In summary, these data show that the overall expression pattern of SHANK is largely conserved in defined brain regions; however, differences do exist, which need to be considered in the translation of rodent studies. The summarized expression patterns of SHANK2 and SHANK3 should serve as a reference for future studies.

Understanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction

“…SHANK3 plays a fundamental role during cerebral development and is highly expressed early during the postnatal course and lifelong for network function; it is a known regulator of the formation and maturation of dendritic spines and integral to synaptic plasticity ( 53 , 73 ). Although systematic regional abundance of SHANK3 in the human brain has not been evaluated, a recent study has identified high levels of expression of the protein in the cortex, hippocampus, and cerebellum in mouse, with expression predominantly in neuronal layers associated with excitatory neurotransmission ( 87 ). Furthermore, white matter evaluations reveal aberrant connectivity in the prefrontal cortex in areas associated with social and cognitive function in both humans and pre-clinical models ( 88 , 89 ).…”