Abstract
Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer’s disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.
Highlights
The Shank family proteins, Shank1, 2, and 3, serve as the core apparatus of postsynaptic protein network (Monteiro and Feng, 2017; Mossa et al, 2018)
We further show examples of the altered laminar and cellular pattern of Shank3 IR observed in representative brain regions in aged and Alzheimer’s disease (AD) cases
Quantitative immunoblot data are presented in support of the immunohistochemical observations, especially regarding the differential regional expression of Shank3 and the decline of its expression with age
Summary
The Shank family proteins, Shank , and 3, serve as the core apparatus of postsynaptic protein network (Monteiro and Feng, 2017; Mossa et al, 2018). These scaffolding proteins regulate the targeting, anchoring, and functioning of neurotransmitter receptors and other signaling molecules, especially at excitatory synapses, thereby playing critical neurobiological roles in synapse formation, plasticity, and transmission (MacGillavry et al, 2016; Wang et al, 2017; Bey et al, 2018; Guo et al, 2019). Shank mRNA expression is enriched in the hippocampal formation, thalamus, striatum, and cerebellar granule cells (Peça et al, 2011; Monteiro and Feng, 2017)
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