Astrocyte‐ and NMDA receptor‐dependent slow inward currents differently contribute to synaptic plasticity in an age‐dependent manner in mouse and human neocortex

Abstract

Slow inward currents (SICs) are known as excitatory events of neurons elicited by astrocytic glutamate via activation of extrasynaptic NMDA receptors. By using slice electrophysiology, we tried to provide evidence that SICs can elicit synaptic plasticity. Age dependence of SICs and their impact on synaptic plasticity was also investigated in both on murine and human cortical slices. It was found that SICs can induce a moderate synaptic plasticity, with features similar to spike timing‐dependent plasticity. Overall SIC activity showed a clear decline with aging in humans and completely disappeared above a cutoff age. In conclusion, while SICs contribute to a form of astrocyte‐dependent synaptic plasticity both in mice and humans, this plasticity is differentially affected by aging. Thus, SICs are likely to play an important role in age‐dependent physiological and pathological alterations of synaptic plasticity.

Pharmacological Activation of Piezo1 Channels Enhances Astrocyte–Neuron Communication via NMDA Receptors in the Murine Neocortex

“…In the first set of experiments, we tested whether the pharmacological activation of Piezo1 channels is capable of changing the SIC activity on randomly chosen pyramidal neurons from layer V of the barrel field and trunk region of the primary somatosensory cortex, the medial and lateral parietal association cortex and the posterior area of the parietal cortex (Figure 1). SICs were distinguished from spontaneous excitatory postsynaptic potentials (sEPSCs) on the basis of their rise time using 20 ms as a cutoff value [28]. The shortest detected rise time of SICs was 33 ms, and the average was 211.68 ± 30.27 ms in contrast to the rise time of sEPSCs (longest rise time: 9.48 ms, average rise time: 7.56 ± 0.36 ms, p < 0.001).…”

“…Supplementation of the recording solution with Yoda1 did not cause any significant increase in SIC activity, as only a single SIC appeared on one of the neurons (SIC amplitude: 60. As SICs are capable of influencing EPSC parameters [28], EPSCs recorded without SICs in the presence of D-AP5 were analyzed before and after application of Yoda1. The As SICs are capable of influencing EPSC parameters [28], EPSCs recorded without SICs in the presence of D-AP5 were analyzed before and after application of Yoda1.…”

“…As SICs are capable of influencing EPSC parameters [28], EPSCs recorded without SICs in the presence of D-AP5 were analyzed before and after application of Yoda1. The As SICs are capable of influencing EPSC parameters [28], EPSCs recorded without SICs in the presence of D-AP5 were analyzed before and after application of Yoda1. The EPSC frequency with D-AP5 before Yoda1 application was 0.174 ± 0.122 Hz, whereas the amplitude was 10.43 ± 0.88 pA. With Yoda1 application, the frequency was 0.046 ± 0.01 Hz and the amplitude was 10.21 ± 0.59 pA, which did not differ significantly from the results obtained without Yoda1 (n = 7).…”

“…However, as involvement of microglia [16] and astrocytes [40] were shown, these actions might not be fully considered as actions exclusively exerted on neurons. It was previously shown that long-term synaptic plasticity is also altered or mediated by astrocytes [41][42][43], and GluN2B subunits containing NMDA receptor-mediated SICs have a particular role in it [28]. Mechanical (transcranial ultrasound or magneto-acoustic) brain stimulation via Piezo1 activation led to an increase in expression of proteins involved in long-term potentiation including the GluN2B subunit [16].…”

“…Depending on its release and diffusion characteristics, astrocytic glutamate release can lead to a transient increase in neuronal activity by 'slow inward currents' (SICs) [26,27]. These currents might synchronize the excitability of neighboring neurons or elicit timing-dependent synaptic plasticity [28]. Thus, these currents might have physiological actions on the fine tuning of neuronal excitability and synaptic strength, or pathological actions by helping the propagation of the spreading depression [29].…”