คาสิโนไทย How Shank3 Deficiency Causes NMDAR Hypofunction Memory

 

Shank3 is a scaffold protein that links NMDA receptors (NMDARs) to other components in the postsynaptic density (Gao et al., 2013). It is implicated in schizophrenia and autism (Gauthier et al., 2010; Uchino and Waga, 2013; Zhou et al., 2016). Shank3 deficiency has been shown to reduce synaptic currents mediated by NMDARs, but its underlying mechanism remains elusive. While the loss of synaptic NMDARs would certainly reduce the NMDAR-mediated synaptic currents, Shank3 deficiency does not always lead to loss of synaptic NMDARs, but still results in NMDAR hypofunction. A few studies using different genetic manipulations on Shank3 are described below. They all produce NMDAR hypofunction, but most of them did not alter the level of synaptic NMDAR subunits.

  • Knockdown of Shank3 by small interfering RNA (siRNA) results in the NMDAR hypofunction as well as decreased surface expression of GluN1 (NR1) subunits (Duffney et al., 2013).
  • By deleting the Shank3 C-terminal domain (exon 21), Duffney et al. (2015) found reduced levels of synaptic GluN1 and GluN2A in the prefrontal cortex, but Kouser et al. (2013) did not observe significant loss of NMDAR subunits in the hippocampal synapses.
  • Insertion of exon 21 did not alter the levels of synaptic NMDAR subunits (คาสิโนไทยSpeed et al., 2015).
  • Deletion of exons 4-9 produced mixed results, both significant GluN2A reduction (Wang et al., 2011) and no change in NMDAR subunits (Jaramillo et al., 2016) have been reported.

Actin has been demonstrated to be involved in the Shank3-dependent NMDAR hypofunction (Duffney et al., 2013; Duffney et al., 2015). In addition to the loss of synaptic NMDARs, the CABT Hypothesis suggests that the actin-mediated NMDAR hypofunction could also arise from "NMDAR extinction", namely, the blockade of NMDARs by the CABT complex which consists of a CRMP2 monomer and a tubulin heteodimer. The NMDAR extinction is a type of NMDAR desensitization. This specific name comes from the evidence that the blockade of NMDARs by CABT could be the underlying mechanism for the macroscopic memory extinction. This chapter will show that, in the cases without loss of synaptic NMDARs, the Shank3-dependent NMDAR hypofunction could result from NMDAR extinction. A recent study did find that SHANK3 downregulation accelerates memory extinction (Bariselli et al., 2018).

Signaling Cascades to Activate Cofilin

Cofilin is a major actin depolymerizing factor that may bind to filamentous actin (F-actin) and induce severing (Elam et al., 2013). Its activity is directly controlled by the phosphorylation status at Ser-3. Dephosphorylation of Ser-3 leads to cofilin activation. In a canonical pathway, activation of the GTPase Rac1 increases the activities of the p21-activated kinase (PAK) and LIM-domain containing protein kinase (LIMK). LIMK may phosphorylate cofilin at Ser-3, resulting in its inactivation.

Normally, the Shank3 binds with a guanine nucleotide exchange factor called β-PIX which may activate Rac1 (ten Klooster et al., 2006), leading to cofilin inactivation (Soria Fregozo and Pérez Vega, 2012; Figure 4). The Shank3 deficiency makes activation of Rac1 by β-PIX less efficient, thereby increasing cofilin activity, which would cause aberrant F-actin depolymerization. Duffney et al. (2015) proposed that the aberrant F-actin depolymerization might disrupt NMDAR synaptic delivery, consequently leading to NMDAR hypofunction (Figure 21-1). However, as mentioned above, a few studies did not find significant loss of synaptic NMDARs while the NMDAR activity was substantially attenuated by Shank3 deficiency. These results could be explained by the CABT Hypothesis, that is, the aberrant F-actin depolymerization may cause CABT to dissociate from F-actin and bind to the GluN2B-containing NMDARs, consequently blocking the NMDAR currents.

Image

Figure 21-1. Shank3-dependent signaling cascades.
Left: Normal pathway. Binding between Shank3 and β-PIX facilitates Rac1 activation, leading to cofilin phosphorylation at Ser-3, thereby reducing its activity .
Right: Shank3 deficiency makes activation of Rac1 by β-PIX less efficient, consequently increasing cofilin activity to depolymerize F-actin.
This figure was reproduced from Duffney et al. (2015) who proposed that the aberrant F-actin depolymerization might disrupt NMDAR synaptic delivery, resulting in NMDAR hypofunction. Alternatively, the CABT Hypothesis suggests that the aberrant F-actin depolymerization may cause CABT to dissociate from F-actin and bind to the GluN2B-containing NMDARs, consequently blocking the NMDAR currents (Chapter 20).

SHANK3 Downregulation Accelerates Memory Extinction

In support of the hypothesis that the Shank3-dependent NMDAR hypofunction could result from NMDAR extinction, Bariselli et al. (2018) observed that SHANK3 downregulation in the ventral tegmental area (VTA) accelerates the extinction of contextual associations. The CABT complex that causes NMDAR extinction consists of a CRMP2 monomer and a tubulin heteodimer. CRMP2 is encoded by the gene, DPYSL2, which is linked to schizophrenia (Fallin et al., 2005; Pham et al., 2016). Strikingly, memory extinction is impaired in schizophrenia (คาสิโนไทย; Holt et al., 2012).

 

Author: Frank Lee
First published: June, 2018
Last updated: October, 2018