Figure 2.

Panx1 channels modulate neuronal excitability, synaptic transmission and plasticity in hippocampal slices. (A,B) Metabolic autocrine regulation of neuronal activity via Panx1 channels and adenosine. (A) Sample trace showing increased outward current upon reduced extracellular glucose (from 11 to 3 mM) and subsequent reversal to baseline with ¹⁰panx application (100 μM) in CA3 pyramidal neurons. Bar graphs showing the reversal of reduced glucose-induced outward current amplitude with ¹⁰panx (left), and that pretreatment with ¹⁰panx prevented reduced glucose-induced outward current. ^**p < 0.01. (B) Schematic showing a proposed model of purinergic autocrine regulation in CA3 pyramidal neurons. When [ATP]_i is sufficient (1), low [Glucose]_e (2) induces ATP release from Panx1 channels on neurons (3). ATP is then dephosphorylated to adenosine (4) which activates adenosice A₁R rceptors (5). K_ATP channels are then opened leading to a decrease in neuronal excitability. (C–F) Panx1 regulates synaptic transmission, LTP and LTD. (C) Input-Output curves showing increased synaptic transmission in Panx1^−/− (black line) compared to control Panx1^+/+ (dashed line) mice. Such effect was abolished in Panx1^−/− slices treated with 3 μM adenosine (red line). ^*p < 0.01; ^**p < 0.001. (D) LTP evoked by high frequency stimulation (four trains of 10 shocks at 100 Hz every 1 s; HFS) is enhanced in Panx1^−/− (filled gray) compared to control Panx1^+/+ (open gray) mice. Adenosine treatment in Panx1^−/− slices (filled red) restores LTP levels to that of untreated control mice. Figure insets illustrate responses before and 30 min post HFS. Scale bar: 0.5 mV, 10 ms. (E) LTP induced by the delivery of theta burst stimulation protocol (TBS) is increased in adult Panx1^−/− (green) compared to Panx1^+/+ (black) mice, whereas no difference was observed between young mice (+/+, gray; −/−, blue). In the presence of 100 μM probenecid (Panx1 channel blocker; red), only transient LTP was enhanced. (F) Similarly, LTD induced by paired-pulse low frequency stimulation protocol (1Hz for 15 min; PP-LFS) are impaired in adult Panx1^−/− (green) compared to Panx1^+/+ (black) mice, whereas no difference was observed between young equivalent (+/+, gray; −/−, blue). In the presence of 100 μM probenecid, only a transient LTD was observed. Adapted, with permission, from Kawamura et al. (2010) (A,B), Prochnow et al. (2012) (C,D) and Ardiles et al. (2014) (E,F).