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

Abstract

Autism spectrum disorders represent a diverse etiological spectrum that converge on a syndrome characterized by discrepant deficits in developmental domains often highlighted by concerns in socialization, sensory integration, and autonomic functioning. Importantly, the incidence and prevalence of autism spectrum disorders have seen sharp increases since the syndrome was first described in the 1940s. The wide etiological spectrum and rising number of individuals being diagnosed with the condition lend urgency to capturing a more nuanced understanding of the pathogenic mechanisms underlying the autism spectrum disorders. The current review seeks to understand how the disruption of AMPA receptor (AMPAr)-mediated neurotransmission in the cerebro-cerebellar circuit, particularly in genetic autism related to SHANK3 or SYNGAP1 protein dysfunction function and autism associated with in utero exposure to the anti-seizure medications valproic acid and topiramate, may contribute to the disease presentation. Initially, a discussion contextualizing AMPAr signaling in the cerebro-cerebellar circuitry and microstructural circuit considerations is offered. Subsequently, a detailed review of the literature implicating mutations or deletions of SHANK3 and SYNGAP1 in disrupted AMPAr signaling reveals how bidirectional pathogenic modulation of this key circuit may contribute to autism. Finally, how pharmacological exposure may interact with this pathway, via increased risk of autism diagnosis with valproic acid and topiramate exposure and potential treatment of autism using AMPAr modulator perampanel, is discussed. Through the lens of the review, we will offer speculation on how neuromodulation may be used as a rational adjunct to therapy. Together, the present review seeks to synthesize the disparate considerations of circuit understanding, genetic etiology, and pharmacological modulation to understand the mechanistic interaction of this important and complex disorder.

Keywords: AMPA; ASD; SHANK3; SynGAP1; autism; cerebro-cerebellar; circuits; synaptopathy.

Figure 1

Correlation of brain regions with AMPA receptor expression and autism spectrum disorders. Relative density of AMPA receptors in indicated brain regions based on data presented by Schwenk et al. (44) (A). For indicated regions, relative amount of total AMPA amount is 52% cortex, 23% hippocampus, 17% cerebellum, 3% striatum, 2% thalamus, and 2% brainstem (A). Regions implicated in autism spectrum disorders derived from human studies (45, 46) (B).

Figure 2

Schematic representation of post-synaptic compartment in AMPAr-associated dendrites in health and disease. Schematic of wild-type dendritic compartment, see also (51) (A). With disruption of SHANK3 protein, structurally diminished post-synaptic compartments, with decreased size of the PSD and depletion of AMPA receptor number is observed (B; (–56)). In contrast, SYNGAP1 dysfunction leads to increased size (“mushrooming”) of the post-synaptic compartment, increased AMPA receptor number, and enhanced Ras-ERK signaling with concomitant changes in gene expression (C; (–60)). The interactions of valproic acid (VPA) and topiramate include the following: for VPA, epigenetic changes related to histone modifications, activation of the Ras-Erk pathway, and changes in expression of AMPAr-related mRNA expression (D (–63)); for topiramate, the primary interaction includes allosteric inhibition of AMPA receptor function (D; (64)).