Neurons and neuronal activity control gene expression in astrocytes to regulate their development and metabolism

Abstract

The influence that neurons exert on astrocytic function is poorly understood. To investigate this, we first developed a system combining cortical neurons and astrocytes from closely related species, followed by RNA-seq and in silico species separation. This approach uncovers a wide programme of neuron-induced astrocytic gene expression, involving Notch signalling, which drives and maintains astrocytic maturity and neurotransmitter uptake function, is conserved in human development, and is disrupted by neurodegeneration. Separately, hundreds of astrocytic genes are acutely regulated by synaptic activity via mechanisms involving cAMP/PKA-dependent CREB activation. This includes the coordinated activity-dependent upregulation of major astrocytic components of the astrocyte–neuron lactate shuttle, leading to a CREB-dependent increase in astrocytic glucose metabolism and elevated lactate export. Moreover, the groups of astrocytic genes induced by neurons or neuronal activity both show age-dependent decline in humans. Thus, neurons and neuronal activity regulate the astrocytic transcriptome with the potential to shape astrocyte–neuron metabolic cooperation.

Neuroprotective potential of astroglia

“…Another obvious question concerns the extent to which the genetic profile of the astrocyte is set by the neurons with which it directly interacts, and whether astrocytes can be fine‐tuned to “look after” various types of neurons (e.g., cortical pyramidal neurons) versus interneurons versus dopaminergic neurons, and so forth. A very elegant approach to this question has been recently described by Hasel et al, who reported that neuronal activity shapes the genomic profile of co‐cultured astrocytes (Hasel et al, ). The idea in that study was to use co‐cultures of neurones and astrocytes from different species.…”

Neuronal activity induces glutathione metabolism gene expression in astrocytes

“…These genes include the complement of lactate dehydrogenase genes ( Ldha, Ldhb, Ldhc , and Ldhd ), critical enzymes for converting pyruvate to lactate. Interestingly, a recent study by Hasel et al (Hasel et al, 2017), published during the course of our work, also analyzed astrocyte transcriptomes in neuronal co-culture. Their approach relied on RNA profiling followed by in silico species separation between mouse astrocytes and rat neurons.…”

“…Further, certain glutamate transporter (Swanson et al, 1997) and connexin (Koulakoff, Ezan, & Giaume, 2008) genes were induced in astrocytes in neuronal co-cultures. It is not clear whether these particular neuronal gene inductions in astrocytes were isolated events or represented more global transcriptional changes in astrocytes, but the broad effects of neuronal sonic hedgehog signaling on Bergmann glia function in the cerebellum suggested the latter might be the case (Farmer et al, 2016), and a recent culture study provided more support for such broad transcriptional changes (Hasel et al, 2017). …”

Synaptic energy metabolism and neuronal excitability, in sickness and health

“…Despite evidence that these cells rely mostly on glucose or its byproducts (ie, lactate) to fuel neurotransmission, it remains unclear how these energy substrates are provided to and used by each cell type under different levels of synaptic activity. Specifically, it is still a matter of debate whether neurons use primarily glucose or astrocyte‐produced lactate to satisfy their high energy demands during increased activity …”