Control of Dendritic Integration and Aversive Reversal Learning by Astrocytic Endocannabinoid Receptors

Kirsten Bohmbach¹, Eva Maria Schönhense¹, Nicola Masala², Andreas Zimmer³, Thoralf Opitz², Heinz Beck², Christian Henneberger¹

¹ Institute of Cellular Neurosciences, University of Bonn Medical School, Bonn, Germany
² Dept. of Epileptology, University of Bonn Medical School, Bonn, Germany
³ Institute of Mol. Psychiatry, University of Bonn, Bonn, Germany

Dendrites of hippocampal CA1 pyramidal cells (PCs) integrate local synaptic input. Supra-linear integration of spatially clustered CA3-CA1 input depends on amplification by voltage-gated sodium channels and N-methyl-D-aspartate receptors (NMDARs). At the same time, NMDAR function depends on astrocytic supply of the NMDAR co-agonist D-serine. Thus, NMDAR-dependent supra-linear integration should also depend on co-agonist supply. We used whole-cell patch clamp combined with micro-iontophoretic glutamate application and two-photon excitation fluorescence microscopy to test this hypothesis in acute hippocampal slices. We find that application of D-serine reduces the threshold of dendritic spikes and increases their amplitude. D-serine supply depends on astrocyte Ca²⁺ signaling, which can be triggered through endocannabinoid receptors (CB1R). As expected, application of a CB1R agonist induced Ca²⁺ transients in astrocytes and promoted supra-linear integration. Also, endogenous endocannabinoids, released by stimulation of CA1 PCs axons, lowered the threshold of dendritic spikes. This effect was not seen in the presence of exogeneous D-serine, D-amino acid oxidase or an inverse CB1R agonist. Interestingly, the boost could only be observed when CA1 PC axons were stimulated at 10Hz but not at 40Hz and was sensitive to inhibition of HCN-channels. Finally, an astrocyte-specific knockout of CB1Rs prevented the effects on dendritic integration and, importantly, led to a selective impairment of reversal learning in a passive place avoidance task.

In summary, we reveal a novel behaviorally relevant signaling pathway that creates a frequency-dependent positive feedback of CA1 PC population activity on their dendritic integration that involves astrocytic CB1R-dependent supply of the NMDAR co-agonist D-serine.