Stress gates an astrocytic energy reservoir to impair synaptic plasticity

Ciaran Murphy-Royal,Govind Peringod,Baljit S Khakh,Grant R Gordon,Jaideep S Bains,Andrew K J Boyce,Oliver Zhang,Adam Institoris,Randy F Stout,Blanca Diaz-Castro,Roger J Thompson,April D Johnston,David C Spray

doi:10.1038/s41467-020-15778-9

Ciaran Murphy-Royal, Govind Peringod + Show 11 more

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https://doi.org/10.1038/s41467-020-15778-9

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Astrocytes support the energy demands of synaptic transmission and plasticity. Enduring changes in synaptic efficacy are highly sensitive to stress, yet whether changes to astrocyte bioenergetic control of synapses contributes to stress-impaired plasticity is unclear. Here we show in mice that stress constrains the shuttling of glucose and lactate through astrocyte networks, creating a barrier for neuronal access to an astrocytic energy reservoir in the hippocampus and neocortex, compromising long-term potentiation. Impairing astrocytic delivery of energy substrates by reducing astrocyte gap junction coupling with dominant negative connexin 43 or by disrupting lactate efflux was sufficient to mimic the effects of stress on long-term potentiation. Furthermore, direct restoration of the astrocyte lactate supply alone rescued stress-impaired synaptic plasticity, which was blocked by inhibiting neural lactate uptake. This gating of synaptic plasticity in stress by astrocytic metabolic networks indicates a broader role of astrocyte bioenergetics in determining how experience-dependent information is controlled.

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Astrocytes support the energy demands of synaptic transmission and plasticity
Using mice expressing an exogenous HA tag on ribosomes (Rpl22HA) in astrocytes (Aldh1l1-cre/ERT2 x Ribotag mice) we sequenced polysomic mRNA from the neocortex of naïve mice and mice subjected to a 20-min swim stress followed by a 90-min recovery (Fig. 1a, b)
Comparing the astrocyte translatome between naïve and stressed mice revealed 117 genes that were differentially affected by acute stress (Fig. 1c and Supplementary Table 1, n = 4 mice in each group)

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Astrocytes support the energy demands of synaptic transmission and plasticity. Enduring changes in synaptic efficacy are highly sensitive to stress, yet whether changes to astrocyte bioenergetic control of synapses contributes to stress-impaired plasticity is unclear. Upstream of the local delivery of lactate to synapses, astrocytes have broader reach by moving lactate across gap junction channels to other astrocytes[24] This effectively creates a distributed energy reservoir that is shared among a network of astrocytes to shuttle lactate to active synapses on demand. We show that acute stress modifies astrocyte structure and function, inducing hypertrophy and decreasing gap junction coupling between cells This stress-induced decrease in coupling effectively isolates individual astrocytes from their network, reducing their capacity to supply neurons with L-lactate, resulting in a decrease in LTP of synaptic transmission. In support of this observation, we show that genetic manipulation of astrocytic gap junction channel function alone, without altering astrocyte morphology, was sufficient to reproduce synaptic deficits. This work sheds light on a key role of astrocytes in limiting synaptic function in response to a single stressful event

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