Neurosteroids are produced in the brain independently of peripheral endocrine glands and act on neurons and glia. They have important roles in mental health-related disorders with great potential for neuropsychopharmacological applications. We have recently demonstrated a novel presynaptic effect of neurosteroids that could help explain their mechanism of action. We found that pregnenolone sulfate (PREGS) enhances facilitated glutamate release in mature neurons and increases tonic glutamate release in immature neurons. We thus propose the following hypothesis: The modulation of glutamate release by neurosteroids is developmentally regulated. In the neonatal brain, neurosteroids enhance maturation of hippocampal circuits while, in the adult brain, neurosteroids modulate signal filtering and short-term plasticity in these same circuits. We will test this hypothesis with two specific aims. (1) To characterize the mechanism of the PREGS-induced enhancement of tonic glutamate release in the neonatal hippocampus and to determine its impact. We have shown that PREGS increases mEPSC frequency in cultured hippocampal neurons and hippocampal slices from neonatal rats. Our goal here is to show that unique characteristics of immature neurons allow the same endogenous neurosteroids to subserve very different functions in neonatal synaptic terminals from those that they will ultimately play in adult neurons. Specifically, we will characterize the effect on PREGS on glutamate release, investigate its effect on silent synapses, and determine its role in modulating synchronous potentials. (2) Investigate the mechanisms by which PREGS enhances short term facilitation of presynaptic glutamate release in the adult hippocampus. We have shown that PREGS causes an enhancement of the bandpass filtering characteristics of the Schaffer to CA1 synapses and also produces a very dramatic frequency-dependent effect on signal transmission through the perforant path to dentate synapses. These effects must contribute significantly to the documented modulation that neurosteroids exert on the processing of spatial/relational information by the hippocampus. Our goal here will be to determine the effect of PREGS on presynaptic Ca2+ dynamics, focus on effects in the CAS field, and determine the functional consequences of PREGS acting at presynaptic glutamatergic terminals in the adult hippocampus. Finally we will confirm that our findings in the in vitro slice also apply to the in vivo hippocampus.
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