Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits that modulate AMPA receptor trafficking, gating and pharmacology throughout the brain. Why cornichon-2 (CNIH-2), another AMPA receptor-associated protein, modulates AMPA receptor gating and pharmacology in hippocampal neurons but not cerebellar granule neurons remains unresolved. Here, we report that CNIH-2 differentially impacts Type-Ia (γ-2 or γ-3) vs. Type-Ib (γ-4 or γ-8) TARP-containing AMPA receptors. Specifically, with AMPA receptors comprising γ-2, the cerebellar-enriched TARP isoform, CNIH-2 decreases IKA/IGlu ratio and decreases cyclothiazide efficacy while having minimal impact on recovery from desensitization and deactivation kinetics. By contrast, with AMPA receptors comprising γ-8, the hippocampal-enriched TARP isoform, we find that CNIH-2 slows deactivation kinetics, increases cyclothiazide potency and occludes a novel AMPA receptor kinetic phenomenon, namely resensitization. Additionally, we find that CNIH-2 differentially modulates the glutamate off-kinetics of γ-8-containing, but not γ-2-containing, AMPA receptors in a manner dependent upon the duration of agonist application. Together, these data demonstrate that the modulation of AMPA receptors by CNIH-2 depends upon the TARP isoform composition within the receptor complex.