Early-life seizures alter synaptic calcium-permeable AMPA receptor function and plasticity

Calcium (Ca²⁺)-mediated⁴ signaling pathways are critical to synaptic plasticity. In adults, the NMDA glutamate receptor (NMDAR) represents a major route for activity-dependent synaptic Ca²⁺ entry. However, during neonatal development, when synaptic plasticity is particularly high, many AMPA glutamate receptors (AMPARs) are also permeable to Ca²⁺ (CP-AMPAR) due to low GluA2 subunit expression, providing an additional route for activity- and glutamate-dependent Ca²⁺ influx and subsequent signaling. Therefore, altered hippocampal Ca²⁺ signaling may represent an age-specific pathogenic mechanism. We thus aimed to assess Ca²⁺ responses 48h after hypoxia-induced neonatal seizures (HS) in postnatal day (P)10 rats, a post-seizure time point at which we previously reported LTP attenuation. We found that Ca²⁺ responses were higher in brain slices from post-HS rats than in controls and that this increase was CP-AMPAR-dependent. To determine whether synaptic CP-AMPAR expression was also altered post-HS, we assessed the expression of GluA2 at hippocampal synapses and the expression of long-term depression (LTD), which has been linked to the presence of synaptic GluA2. Here we report a decrease 48h after HS in synaptic GluA2 expression at synapses and LTD in hippocampal CA1. Given the potentially critical role of AMPAR trafficking in disease progression, we aimed to establish whether post-seizure in vivo AMPAR antagonist treatment prevented the enhanced Ca²⁺ responses, changes in GluA2 synaptic expression, and diminished LTD. We found that NBQX treatment prevents all three of these post-seizure consequences, further supporting a critical role for AMPARs as an age-specific therapeutic target.