The Role of Zinc and NMDA Receptors in Autism Spectrum Disorders

Abstract

NMDA-type glutamate receptors are critical for synaptic plasticity in the central nervous system. Their unique properties and age-dependent arrangement of subunit types underpin their role as a coincidence detector of pre- and postsynaptic activity during brain development and maturation. NMDAR function is highly modulated by zinc, which is co-released with glutamate and concentrates in postsynaptic spines. Both NMDARs and zinc have been strongly linked to autism spectrum disorders (ASDs), suggesting that NMDARs are an important player in the beneficial effects observed with zinc in both animal models and children with ASDs. Significant evidence is emerging that these beneficial effects occur via zinc-dependent regulation of SHANK proteins, which form the backbone of the postsynaptic density. For example, dietary zinc supplementation enhances SHANK2 or SHANK3 synaptic recruitment and rescues NMDAR deficits and hypofunction in Shank3ex13–16−/− and Tbr1+/− ASD mice. Across multiple studies, synaptic changes occur in parallel with a reversal of ASD-associated behaviours, highlighting the zinc-dependent regulation of NMDARs and glutamatergic synapses as therapeutic targets for severe forms of ASDs, either pre- or postnatally. The data from rodent models set a strong foundation for future translational studies in human cells and people affected by ASDs.

Effect of chronic F- exposure on ionotropic glutamate AMPA and NMDA receptors in rat hippocampus

“…suggested neuroprotective function of hippocampal astrocytic NMDARs since pharmacological antagonism of GluN2A and GluN2B exacerbates β-amyloid (Aβ) induced synaptotoxicity, while knockdown of Grin2a gene aggravated cognitive decline induced by sleep deprivation or application of Aβ. The bene cial role of modulating NMDARs activities was proposed for correction of autism spectrum disorders and emotional disorders like anxiety and depression[76,77]. The results obtained in our study indicate that long-term F − consumption leads to considerable alterations in NMDARs subunit composition and subcellular distribution in rat hippocampal cells which might disturb the synaptic functions.…”

Advances in the Treatment of Autism Spectrum Disorder: Current and Promising Strategies

“…The N-methyl-D-aspartate (NMDA) receptor is a type of glutamate receptor that plays a critical role in regulating synaptic plasticity and is important for learning and memory. Evidence suggests that abnormalities in NMDA receptor signaling may contribute to the development of ASD [ 31 ].…”

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

“…SHANK3 has five interaction domains including a Sterile a motif domain, a proline-rich domain, an src domain, an ankyrin repeats domain, and a PDZ domain, which aid in SHANK3-mediated trafficking of N-methyl-D-aspartate (NMDA) and AMPA receptors (PDZ mediates interactions with NMDA and AMPA receptors via GKAP, but the SH3 domain may directly interact with AMPA receptors and the SAM domain may additionally interact with GKAP and affect NMDA receptors) ( 53 – 55 ) ( Figure 2B ). As mentioned above, disruption of AMPAr function has broad influences on processes implicated in autism pathogenesis including synapse development, LTP, and LTD. SHANK3 has also been found to influence dendritic spine morphology through a mechanism of NMDA receptor expression and AMPA receptor [rapid] recycling ( 92 ) ( Figure 2B ). Furthermore, mutations in Shank3 have been shown to result in depletion of AMPA receptors and a change in morphology of the PSD ( 52 , 56 ).…”