An astrocytic signaling loop for frequency-dependent control of dendritic integration and spatial learning

Abstract

Dendrites of hippocampal CA1 pyramidal cells amplify clustered glutamatergic input by activation of voltage-gated sodium channels and N-methyl-D-aspartate receptors (NMDARs). NMDAR activity depends on the presence of NMDAR co-agonists such as D-serine, but how co-agonists influence dendritic integration is not well understood. Using combinations of whole-cell patch clamp, iontophoretic glutamate application, two-photon excitation fluorescence microscopy and glutamate uncaging we found that exogenous D-serine reduces the threshold of dendritic spikes and increases their amplitude. Triggering an astrocytic mechanism controlling endogenous D-serine supply via endocannabinoid receptors (CBRs) also increased dendritic spiking. Unexpectedly, this pathway was activated by pyramidal cell activity primarily in the theta range, which required HCN channels and astrocytic CB1Rs. Therefore, astrocytes close a positive and frequency-dependent feedback loop between pyramidal cell activity and their integration of dendritic input. Its disruption led to an impairment of spatial memory, which demonstrates its behavioral relevance.

Centripetal integration of past events by hippocampal astrocytes and its regulation by the locus coeruleus

“…A possible astrocytic output signal that could fulfil this role and warrants further investigation in the context of centripetal integration is gliotransmission, the astrocytic release of e.g. glutamate [67][68][69][70] , D-serine 59,60,71 or lactate 72,73 , in particular since this process has been found to be prominently involved in neuronal plasticity 56,74 . Centripetal integration of past events in astrocytes therefore seems to be a plausible candidate mechanism to conditionally mediate or modulate neuronal plasticity on a behavioral time scale.…”