Synaptic activation of NMDA receptors plays a key role in synaptic plasticity and can be neuroprotective. On the other hand, excessive tonic NMDAR activation mediates excitotoxicity. This paradoxical involvement of NMDARs in both neuroprotection and neurotoxicity motivates an interest in pharmacological agents selectively blocking pathological NMDAR signaling while leaving normal synaptic transmission intact. Endogenous neurosteroid pregnanolone sulfate (PA-S) inhibits NMDARs in a use-dependent manner, and at the same time potentiates presynaptic glutamate release. These properties predict that PA-S may selectively inhibit tonically over synaptically activated NMDARs and thus be neuroprotective. We use synaptic electrophysiology to characterize presynaptic and postsynaptic effects of PA-S and PA-S analogues. Using in-vitro excitotoxicity models we aim to identify an optimal combination of steroid synaptic effects for maximal neuroprotection.
Recordings of evoked excitatory postsynaptic currents in hippocampal microisland cultures reveal bidirectional modulation of synaptic NMDA receptors by neurosteroids.