ATP released from astrocytes modulates action potential threshold and spontaneous excitatory postsynaptic currents in the neonatal rat prefrontal cortex

Abstract

Maternal immune activation during pregnancy is a risk factor for neurodevelopmental disorders, such as schizophrenia; however, a full mechanistic understanding has yet to be established. The activity of a transient cell population, the subplate neurons, is critical for the development of cortical inhibition and functional thalamocortical connections. Sensitivity of these cells to factors released during inflammation, therefore, may offer a link between maternal immune activation and the aberrant cortical development underlying some neuropsychiatric disorders. An elevated extracellular ATP concentration is associated with inflammation and has been shown to have an effect on neuronal activity. Here, we investigated the effect of ATP on the electrophysiological properties of subplate neurons. Exogenous ATP increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) at micromolar concentrations. Further, ATP released by astrocytes activated by the PAR-1 agonist, TFLLR-NH₂, also increased the amplitude and frequency of sEPSCs in subplate neurons. The electrophysiological properties of subplate neurons recorded from prefrontal cortical (PFC) slices from neonatal rats were also disrupted in a maternal immune activation rat model of schizophrenia, with a suramin-sensitive increase in frequency and amplitude of sEPSCs. An alternative neurodevelopmental rat model of schizophrenia, MAM-E17, which did not rely on maternal immune activation, however, showed no change in subplate neuron activity. Both models were validated with behavioral assays, showing schizophrenia-like endophenotypes in young adulthood. The purinergic modulation of subplate neuron activity offers a potential explanatory link between maternal immune activation and disruptions in cortical development that lead to the emergence of neuropsychiatric disorders.

Keywords: ATP; Astrocyte; P2X7 receptor; Schizophrenia; Subplate neuron; Suramin.