Calcium-permeable AMPA receptors govern PV neuron feature selectivity

The brain helps us survive by forming internal representations of the external world^1,2. Excitatory cortical neurons are often precisely tuned to specific external stimuli^3,4. However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective⁵. PV interneurons differ from excitatory cells in their neurotransmitter receptor subtypes, including AMPA receptors^6,7. While excitatory neurons express calcium-impermeable AMPA receptors containing the GluA2 subunit, PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find a low expression stoichiometry of GluA2 mRNA relative to other subunits in PV interneurons which is conserved across ferrets, rodents, marmosets, and humans, causing abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Sparse CP-AMPAR manipulations demonstrated that this increase was cell-autonomous and could occur well beyond development. Interestingly, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, suggesting that the selectivity of PV interneurons can be altered without drastically changing connectivity. In GluA2 knockout mice, where all AMPARs are calcium-permeable, excitatory neurons showed significantly reduced orientation selectivity, suggesting that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Remarkably, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, indicating that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a novel role of CP-AMPARs in maintaining a low-selectivity sensory representation in PV interneurons and suggest a conserved molecular mechanism that distinguishes the unique synaptic computations of inhibitory and excitatory neurons.