Synaptic NMDA receptors mediate hypoxic excitotoxic death.

Excessive NMDA receptor activation and excitotoxicity underlies pathology in many neuropsychiatric and neurological disorders, including hypoxia/ischemia. Thus, the development of effective therapeutics for these disorders demands a complete understanding of NMDA receptor (NMDAR) activation during excitotoxic insults. The extrasynaptic NMDAR hypothesis posits that synaptic NMDARs are neurotrophic/neuroprotective and extrasynaptic NMDARs are neurotoxic.

Excitotoxicity triggered by Neurobasal culture medium.

Neurobasal defined culture medium has been optimized for survival of rat embryonic hippocampal neurons and is now widely used for many types of primary neuronal cell culture. Therefore, we were surprised that routine medium exchange with serum- and supplement-free Neurobasal killed as many as 50% of postnatal hippocampal neurons after a 4 h exposure at day in vitro 12-15. Minimal Essential Medium (MEM), in contrast, produced no significant toxicity.

Presynaptic silencing is an endogenous neuroprotectant during excitotoxic insults.

Glutamate release is a root cause of acute and delayed neuronal damage in response to hypoxic/ischemic insults. Nevertheless, therapeutics that target the postsynaptic compartment have been disappointing clinically. Here we explored whether presynaptic silencing (muting) of glutamatergic terminals is sufficient to reduce excitotoxic damage resulting from hypoxia and oxygen/glucose deprivation.

Effects on membrane capacitance of steroids with antagonist properties at GABAA receptors.

We investigated the electrophysiological signature of neuroactive steroid interactions with the plasma membrane. We found that charged, sulfated neuroactive steroids, those that exhibit noncompetitive antagonism of GABA(A) receptors, altered capacitive charge movement in response to voltage pulses in cells lacking GABA receptors. Uncharged steroids, some of which are potent enhancers of GABA(A) receptor activity, produced no alteration in membrane capacitance.