Astroglial Cx30 differentially impacts synaptic activity from hippocampal principal cells and interneurons

Abstract

Astrocytes play important roles in brain function via dynamic structural and functional interactions with neurons. Yet the underlying mechanisms remain poorly defined. A typical feature of astrocytes is the high expression of connexins, which mediate their extensive intercellular communication and regulate their structural properties. In particular, connexin 30 (Cx30), one of the two connexins abundantly expressed by astrocytes, was recently shown to be a critical regulator of excitatory synaptic transmission by controlling the astroglial coverage of synapses. However, the role of Cx30 in the regulation of inhibitory synaptic transmission and excitatory/inhibitory balance remains elusive. Here, we investigated the role of astroglial Cx30 on the electrophysiological and morphological properties of five classes of hippocampal CA1 stratum oriens and pyramidale neurons, defined by the unsupervised Ward's clustering. Using Cx30 knockout mice, we found that Cx30 alters specific properties of some subsets of CA1 interneurons, such as resting membrane potential and sag ratio, while other parameters, such as action potential threshold and saturation frequency, were more frequently altered among the different classes of neurons. The excitation‐inhibition balance was also differentially and selectively modulated among the different neuron subtypes. Only slight morphological differences were observed on reconstructed neurons. Altogether, these data indicate that Cx30 differentially alters the electrophysiological and morphological properties of hippocampal cell populations, and modulates both their excitatory and inhibitory inputs. Astrocytes, via Cx30, are thus active modulators of both excitatory and inhibitory synapses in the hippocampus.

The IgCAM BT-IgSF (IgSF11) Is Essential for Connexin43-Mediated Astrocyte–Astrocyte Coupling in Mice

“…The close contact of astrocytic branches with synapses allows astrocytes to sense neuronal activity via their ion channels and neurotransmitter receptors ( Ventura and Harris, 1999 ). Disruption of astrocytic networks, for example, by inactivation of connexin43 and connexin30 reduced synaptic transmission ( Perea et al, 2009 ; Giaume et al, 2010 ; Pannasch et al, 2011 ; Pereda, 2014 ; Charvériat et al, 2017 ; Hardy et al, 2021 ). Accordingly, connexin30 and astrocyte-targeted connexin43 knock-out mice as well as connexin43 and connexin30 double knock-out mice display impaired performance in sensorimotor and spatial memory tasks ( Theis et al, 2003 ; Lutz et al, 2009 ).…”

Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory

“…Physiologically, it has already been shown that hippocampal Cx30 protein levels, as well as astrocytic network size, can be modulated by neuronal activity [ 18 , 37 ], suggesting that there is a close relationship between astrocytic network size and the activation of underlying neuronal networks. However, this modulation is complex, as it differentially impacts the principal cells and the interneurons [ 23 ]. In addition, Cx30 can also act via other mechanisms, such as signaling and protein interactions.…”

“…However, the number of action potentials evoked by depolarizing pulses was lower in CA1 pyramidal cells from AAV-GFAP-Cx30-injected mice (Fig 5C). Previous work on mice deficient for astroglial connexins reported a decrease in the amplitude and duration of CA1 pyramidal cells afterhyperpolarization (AHP) [23][24][25], i.e., the refractory period following action potential discharges during which neuron membrane potential is hyperpolarized (undershoot). We thus investigated AHP in mice with upregulated Cx30 and found an increased amplitude (approximately 40%) and duration (approximately 15%).…”

The IgCAM BT-IgSF (IgSF11) is essential for connexin43-mediated astrocyte-astrocyte and ependymal cell-cell coupling in mice

“…The close contact of astrocytic branches with synapses allows astrocytes to sense neuronal activity via their ion channels and neurotransmitter receptors (Ventura and Harris, 1999). Disruption of astrocytic networks for example by inactivation of connexin43 and 30 reduced synaptic transmission (Charvériat et al, 2017; Giaume et al, 2010; Hardy et al, 2021; Pannasch et al, 2011; Perea et al, 2009; Pereda, 2014). Accordingly, connexin30 and astrocyte-targeted connexin43 knockout mice as well as connexin43 and 30 double knockout mice display impaired performance in sensorimotor and spatial memory tasks (Lutz et al, 2009; Theis et al, 2003).…”