Distinct contributions of GluA1-containing AMPA receptors of different hippocampal subfields to salience processing, memory and impulse control

Abstract

Schizophrenia is associated with a broad range of severe and currently pharmacoresistant cognitive deficits. Prior evidence suggests that hypofunction of AMPA-type glutamate receptors (AMPARs) containing the subunit GLUA1, encoded by GRIA1, might be causally related to impairments of selective attention and memory in this disorder, at least in some patients. In order to clarify the roles of GluA1 in distinct cell populations, we investigated behavioural consequences of selective Gria1-knockout in excitatory neurons of subdivisions of the prefrontal cortex and the hippocampus, assessing sustained attention, impulsivity, cognitive flexibility, anxiety, sociability, hyperactivity, and various forms of short-term memory in mice. We found that virally induced reduction of GluA1 across multiple hippocampal subfields impaired spatial working memory. Transgene-mediated ablation of GluA1 from excitatory cells of CA2 impaired short-term memory for conspecifics and objects. Gria1 knockout in CA3 pyramidal cells caused mild impairments of object-related and spatial short-term memory, but appeared to partially increase social interaction and sustained attention and to reduce motor impulsivity. Our data suggest that reduced hippocampal GluA1 expression—as seen in some patients with schizophrenia—may be a central cause particularly for several short-term memory deficits. However, as impulse control and sustained attention actually appeared to improve with GluA1 ablation in CA3, strategies of enhancement of AMPAR signalling likely require a fine balance to be therapeutically effective across the broad symptom spectrum of schizophrenia.

Multiple serum anti-glutamate receptor antibody levels in clozapine-treated/naïve patients with treatment resistant schizophrenia

“…Numerous studies have shown that NMDAR dysfunction may be involved in the pathogenesis of schizophrenia and is widely associated with psychotic symptoms and cognitive impairment [44]. In addition to NMDAR dysfunction, AMPAR dysfunction mentioned in this study has been associated with selective attention and memory impairment in schizophrenia [45]. The activation of mGluR3 in the prefrontal cortex plays an important role in working memory and cognition[46], and variation in GRM3, the gene encoding mGlu3, has been shown to be associated with schizophrenia and cognitive de cits [47].…”

Air pollution nanoparticle and alpha-synuclein fibrils synergistically decrease glutamate receptor A1, depending upon nPM batch activity

“…GluA1 is a postsynaptic membrane receptor mediating the glutamate signaling and synaptic function [ 37 ]; its deficiency leads to behavioral abnormalities, declined learning and memory, and impaired short-term olfaction memory [ 38 , [60] , [61] , [62] ]. Gria1 expression did not decrease after exposure to any of the three nPM batches alone.…”

Neuronal Activation of the Gαq Protein EGL-30/GNAQ Late in Life Rejuvenates Cognition Across Species

“…We also found genes that regulate synapse activity, many of which have direct involvement in long-term potentiation, were upregulated; for example, Grin1/nmr-1 encodes for GluN1, an essential component of the NMDA receptor, and alternative splicing of Grin1 exon 5 controls the magnitude of long-term potentiation in CA1, and thus the ability to learn and remember (40). Gria1 encodes for the GluA1 AMPA receptor subunit, and reduction of GluA1 in CA2/CA3 impairs short-term memory (41).…”