Gain-of-function glutamate receptor interacting protein 1 variants alter GluA2 recycling and surface distribution in patients with autism

Abstract

Glutamate receptor interacting protein 1 (GRIP1) is a neuronal scaffolding protein that interacts directly with the C termini of glutamate receptors 2/3 (GluA2/3) via its PDZ domains 4 to 6 (PDZ4-6). We found an association (P < 0.05) of a SNP within the PDZ4-6 genomic region with autism by genotyping autistic patients (n = 480) and matched controls (n = 480). Parallel sequencing identified five rare missense variants within or near PDZ4-6 only in the autism cohort, resulting in a higher cumulative mutation load (P = 0.032). Two variants correlated with a more severe deficit in reciprocal social interaction in affected sibling pairs from proband families. These variants were associated with altered interactions with GluA2/3 and faster recycling and increased surface distribution of GluA2 in neurons, suggesting gain-of-function because GRIP1/2 deficiency showed opposite phenotypes. Grip1/2 knockout mice exhibited increased sociability and impaired prepulse inhibition. These results support a role for GRIP in social behavior and implicate GRIP1 variants in modulating autistic phenotype.

Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade

“…PICK1 competes with GRIP1 for binding to the same region of the GluA2 C-tail, in a manner regulated by GluA2 phosphorylation (32). In general, GRIP1 and PICK1 are thought to have opposing roles in AMPAR trafficking, with GRIP1 promoting forward trafficking of GluA2-containing AMPA receptors to synapses (15,17,21,22,32) and PICK1 triggering internalization (23,33,45). Phosphorylation of GluA2 on amino acids 876 by the tyrosine kinase lyn (43) or 880 by PKC (32) blocks GRIP1 binding but leaves PICK1 binding unperturbed.…”

“…Together, these data suggest that the interaction between GluA2 and GRIP1 is required for the expression of synaptic scaling. Because there is some evidence that GRIP1 is important for basal trafficking of AMPA receptors (21,32,44), we also examined whether the GluA2 mutants on a GluA2 KD background affected the baseline amplitude of mEPSCs. None of these mutations on a GluA2KD background induced any significant change in mEPSC amplitude compared with nontransfected neurons, suggesting that basal trafficking is unperturbed ( Fig.…”

“…Several trafficking proteins are known to interact with the GluA2, but not the GluA1, C-tail, including glutamate receptor interacting protein-1 (GRIP1) (15) and protein interacting with C-kinase-1 (PICK1) (16). Many studies have examined the role of GRIP1 and PICK1 in AMPAR trafficking and surface accumulation (15,(17)(18)(19)(20)(21)(22), but little is known about their potential roles in regulating AMPAR synaptic accumulation during synaptic scaling. It was recently shown that deletion of PICK1, which competes with GRIP1/2 for binding to GluA2, enhances AMPAR accumulation and occludes synaptic scaling up (23), suggesting GRIP/PICK1-GluA2 interactions as possible critical players in synaptic scaling.…”

“…How GRIP1 influences basal AMPAR trafficking is not entirely clear. Overexpression of GRIP1 or gain-of-function GRIP1 mutants have been consistently observed to enhance surface AMPAR levels (21,31), but knockout or dominant-negative GRIP1 constructs have had inconsistent effects, with slower synaptic AMPAR accumulation Significance Brain circuits need plasticity mechanisms that stabilize activity to function properly. Although such homeostatic plasticity mechanisms have been widely described in a number of brain circuits, little is known about the molecular pathways that mediate them.…”

GRIP1 is required for homeostatic regulation of AMPAR trafficking

“…Several variants of GRIP1 have been identified in patients with autism, and GRIP1/2 double-knockout mice showed abnormal social behaviors (44). Autism spectrum disorders (ASD) are associated with abnormal synaptogenesis and imbalance between excitatory and inhibitory currents (3,45).…”