Expression of SHANK3 in the Temporal Neocortex of Patients with Intractable Temporal Epilepsy and Epilepsy Rat Models

Abstract

SH3 and multiple ankyrin (ANK) repeat domain 3 (SHANK3) is a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses. SHANK3 plays an important role in the formation and maturation of excitatory synapses. In the brain, SHANK3 directly or indirectly interacts with various synaptic molecules including N-methyl-D-aspartate receptor, the metabotropic glutamate receptor (mGluR), and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Previous studies have shown that Autism spectrum disorder is a result of mutations of the main SHANK3 isoforms, which may be due to deficit in excitatory synaptic transmission and plasticity. Recently, accumulating evidence has demonstrated that overexpression of SHANK3 could induce seizures in vivo. However, little is known about the role of SHANK3 in refractory temporal lobe epilepsy (TLE). Therefore, we investigated the expression pattern of SHANK3 in patients with intractable temporal lobe epilepsy and in pilocarpine-induced models of epilepsy. Immunofluorescence, immunohistochemistry, and western blot analysis were used to locate and determine the expression of SHANK3 in the temporal neocortex of patients with epilepsy, and in the hippocampus and temporal lobe cortex of rats in a pilocarpine-induced epilepsy model. Double-labeled immunofluorescence showed that SHANK3 was mainly expressed in neurons. Western blot analysis confirmed that SHANK3 expression was increased in the neocortex of TLE patients and rats. These results indicate that SHANK3 participates in the pathology of epilepsy.

Overexpression of Homer1b/c induces valproic acid resistance in epilepsy

“…Mutations in gephyrin, an essential core scaffolding protein, have been demonstrated to be involved in the regulation of inhibitory PSD associated with pharmacoresistant epilepsy 38 . Furthermore, the alternative expression of the microtubule units (α‐ and β‐tubulin) and components (SH3 and multiple Ankyrin repeat domains 3, and postsynaptic density protein‐93) of PSD in excitatory neurons has been revealed in latent and chronic epilepsy 39–41 …”

“…38 Furthermore, the alternative expression of the microtubule units (α-and β-tubulin) and components (SH3 and multiple Ankyrin repeat domains 3, and postsynaptic density protein-93) of PSD in excitatory neurons has been revealed in latent and chronic epilepsy. [39][40][41] Homer scaffolding proteins (Homer1-3) are evolutionarily conserved key components of the PSD. Homer 1 is highly expressed in the cortex 42 and hippocampus, 43 which are regions associated with the etiology of epilepsy.…”

G‐alpha interacting protein interacting protein, C terminus 1 regulates epileptogenesis by increasing the expression of metabotropic glutamate receptor 7

“…Thus, we explored the expression patterns of GIPC1 in the brain tissues of patients with TLE and mice with KA-induced epilepsy and our experimental results of reduced GIPC1 also show the possible involvement of GIPC1 in epilepsy. In addition, it has been reported that gene mutations in the GIPC protein family may be associated with the development of myoclonus, primary tremor, and juvenile epilepsy, 14 and previous studies have indicated that many scaffolding proteins [15][16][17] are involved in epilepsy; hence, we speculate that GIPC1 also participates in epilepsy.…”

“…In addition, it has been reported that gene mutations in the GIPC protein family may be associated with the development of myoclonus, primary tremor, and juvenile epilepsy. 14 Furthermore, previous studies have indicated that many scaffolding proteins [15][16][17] are involved in epilepsy; hence, we speculate that GIPC1, a scaffolding protein, also participates in epilepsy. Through binding to various proteins, GIPC1 plays a role in many biological processes such as vesicular trafficking, 13,18 protein transport and expression, [19][20][21] endocytosis, 22 signal transduction, 23,24 and tumorigenesis.…”

SAPAP3 regulates epileptic seizures involving GluN2A in post-synaptic densities

“…More interestingly, recent evidence from human genetic studies also supports a role for SAPAPs in obsessive-compulsive behaviors [13,14]. Shank proteins are synaptic cytoskeleton-associated proteins that interact with SAPAPs, and previous studies identified a role for Shank3 in epilepsy [15][16][17] and indicate that PSD95/SAPAP/Shank multiprotein units might play an important role in organizing the postsynaptic signaling complex at glutamatergic synapses [18,19]. Few studies have investigated SAPAPs in the hippocampus; however, a previous study showed that SAPAP1, SAPAP2, and SAPAP4 transcripts are distributed in the cell body and that SAPAP3 is found in the molecular layers, which indicates that SAPAP3 may contribute to the function of dendritic spines in the hippocampus [20].…”