DETAILING THE HIPPOCAMPAL GABAERGIC CIRCUITS INVOLVED IN MEDIATING THE EFFECTS ON SYNAPTIC PLASTICITY AND NEUROPROTECTION AND MIDAZOLAM-BASED MECHANISMS

Midazolam is widely used for its anxiolytic properties but is associated with postoperative neurocognitive disorders. Previously, we demonstrated that 10nM midazolam blocks long-term potentiation (LTP) via alpha1- and alpha5-containing GABAA receptors (alpha1 and alpha5), whereas in an in vitro hypoxic/hypoglycaemic excitotoxicity (HHE) model alpha5 are mediating neuroprotection. Fast-spiking parvalbumin-positive interneurons (PV-INs) provide perisomatic inhibition to hippocampal pyramidal neurons, primarily via alpha1. In contrast, CA2-LTP is normally resistant to induction, largely due to exceptionally strong PV-IN–mediated inhibition that constrains postsynaptic depolarization.
By means of adeno-associated viral vector (AAV)-mediated neuronal silencing, we investigated the role of PV-INs in neuroprotecion and midazolam’s effects on synaptic plasticity.
PV-INs-silencing per se increased stimulated hippocampal neuronal activity and impairs CA1-LTP. In the CA2 region however, PV-IN-silencing removes the inhibitory constraint and unmasks a latent LTP capacity. Furthermore, silencing PV-INs permits CA1-LTP induction even in the presence of midazolam. Notably, PV-INs-silencing provided neurons to recover in the HHE model.
We conclude that PV-IN-silencing reduces GABAergic tone, thereby increasing CA1 excitability, while the concomitant disruption of network synchronization likely accounts for the impairment of LTP. Abolishing PV-IN function eliminates midazolam’s inhibitory effect on LTP, indicating that PV-INs are required for this suppression, most likely by engaging α1. In the HHE model, PV-IN silencing confers resilience against excitotoxicity, potentially by removing a highly energy-demanding interneuron population and preventing maladaptive or pathological GABAergic excitation. Together, these results identify PV-IN–dependent inhibitory control as critical through which midazolam exerts its bidirectional effects on hippocampal plasticity and neuronal survival.