Figure 7.

Working model for the action of PregS and related neurosteroids at glutamatergic synapses in immature CA1 hippocampal pyramidal cells. (A) Under control conditions, neonatal CA1 hippocampal pyramidal neurons could have a mixture of glutamatergic synapses containing both post-synaptic AMPARs (blue) and NMDARs (red) (active synapses) or only post-synaptic NMDARs (silent synapses at rest). A “silent synapse” is enlarged. Presynaptic NMDARs are shown in orange. (B) PregS increases Ca²⁺ influx through presynaptic NMDARs, leading to an increase in the probability of glutamate release and activation of post-synaptic NMDARs. Pre- and post-synaptic NMDARs at these synapses are proposed to contain NR2D subunits, making them less sensitive to Mg²⁺ block. (C) Glutamate release probability returns to baseline levels after PregS washout. The post-synaptic increase in [Ca²⁺] shown in panel B elicits delayed insertion of AMPARs only in “silent synapses” [From Valenzuela et al. (156) with Permission].