|Memory > How Shank3 Deficiency Causes NMDAR Hypofunction|
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.
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.
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 (Holt et al., 2009; Holt et al., 2012).
Author: Frank Lee