Fig. 1. The D-serine hypothesis.

a, b The astrocytes-mediated feedback loop observed in ref. ³² shows remarkable similarities with the BCM postulate of a synaptic modification threshold θ sliding as a function of the post-synaptic activity y. The feedback loop is described in three steps: (1) endocannabinoids are released by the post-synaptic neuron upon activation, (2) they bind with astrocytic cannabinoid receptors and trigger an intracellular calcium signaling, which results in (3) the release of D-serine at the neuron dendrites. c The increase (decrease) of D-serine concentration at the synapse promotes LTP (LTD), which can be interpreted as the shifting of a threshold for LTP, like the BCM one (figure adapted from ref. ³¹). d The astrocytic regulation of D-serine presents a peculiar bell-shaped dependence on the frequency of post-synaptic stimulation, analogous to the super-linear dependence of the BCM's threshold on the post-synaptic activity. Changes in the D-serine level are indirectly measured through changes in the amplitude of dendritic spikes' slow component (figure adapted from ref. ³²).