INVESTIGATION OF ASTROCYTE ALPHA-1A RECEPTORS IN DENTATE GYRUS PATTERN SEPARATION AND CONTEXTUAL FEAR MEMORY DISCRIMINATION

The ability to encode and discriminate between memories relies on mechanisms that separate the cellular substrates, or “engrams,” of individual memories. Astrocytes not only provide metabolic and structural support to neurons, but also actively influence neuronal activity to promote memory formation via calcium signalling. Noradrenaline (NA) is a primary modulator of astrocyte calcium dynamics, acting through Gq-coupled α1 noradrenergic receptors to induce intracellular calcium release. Here, we investigate the role of noradrenergic astrocyte signalling in contextual fear memory discrimination.
We studied how NA signalling onto astrocytes influences synaptic transmission in the hippocampal dentate gyrus (DG) through electrophysiological recordings obtained from Fgfr3-iCreERT^+/-;Adra1a^f/f mice, with brain-wide astrocyte deletion of α1A receptors. Minimum stimulation experiments demonstrated that activation of astrocytic α1A receptors increased presynaptic glutamate release probability in the perforant path input to the DG.
In follow-up experiments we investigated how NA signalling onto astrocytes influences contextual fear memory discrimination. We utilised Adra1A^f/f mice with bilateral injection of AAV5-GFAabc1d4x6T-Cre to induce astrocyte-specific knockout of α1A receptors in the DG. Mice were conditioned in context A (0.6mA, 2s shock) and tested one day later for memory retrieval in the same context A or a different context B. We used scFLARE2 to achieve light- and activity-dependent labelling of DG neurons during contextual fear conditioning and cFos for neurons that were active during retrieval to test pattern separation in the DG.
Together, this multi-level approach integrates synaptic physiology, engram analysis and behaviour and aims to define the contribution of astrocytic α1A receptors to behavioural memory discrimination.