Wired for change Cannabinoid and GluA3-containing AMPA receptors in cortical synaptic transmission throughout life

Fast glutamatergic signaling is essential for cortical information processing and is primarily mediated by AMPA receptors (AMPARs). Although GluA1-containing AMPARs have been extensively studied, the contribution of GluA3-containing AMPARs to cortical synaptic physiology and their interaction with neuromodulatory systems remain poorly understood. This thesis investigated the role of GluA3-containing AMPARs in sensory and association cortices, their modulation by β-adrenergic signaling, and their potential interaction with cannabinoid receptors (CBRs) during prefrontal cortex (PFC) development.
Using patch-clamp electrophysiology and behavioral approaches, we found that GluA3-containing AMPARs contribute prominently to excitatory synaptic transmission in layer 2/3 pyramidal neurons of the primary visual cortex, whereas their contribution in the medial PFC was dependent on developmental stage and sex. β-adrenergic activation potentiated synaptic transmission in both cortical regions, but through region-specific mechanisms. In the mPFC, GluA3 deficiency was associated with impairments in reversal learning, supporting a role for this subunit in cognitive flexibility. We further showed that repeated CBR activation during adolescence induced persistent, sex-specific alterations in adult mPFC physiology, affecting synaptic transmission in females and intrinsic excitability in males, without producing detectable deficits in social hierarchy or reversal learning.
Finally, a pilot study combining GluA3 deficiency with adolescent CBR activation revealed no clear functional interaction between the two systems, although preliminary findings suggested increased vulnerability in male GluA3KO mice. Together, these findings highlight the region-, developmental stage-, and sex-dependent regulation of cortical synaptic physiology and provide new insight into the contribution of GluA3-containing AMPARs and neuromodulatory systems to cortical function and development.