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. 2023 Jan-Dec:15:17590914231184712.
doi: 10.1177/17590914231184712.

Astrocyte and Neuronal Panx1 Support Long-Term Reference Memory in Mice

Price Obot  1   2 , Galadu Subah  1 , Antonia Schonwald  1 , Jian Pan  1 , Libor Velíšek  1   3   4 , Jana Velíšková  1   5 , Patric K Stanton  1   4 , Eliana Scemes  1
Affiliations

Astrocyte and Neuronal Panx1 Support Long-Term Reference Memory in Mice

Price Obot et al. ASN Neuro. 2023 Jan-Dec.

Abstract

Pannexin 1 (Panx1) is an ubiquitously expressed protein that forms plasma membrane channels permeable to anions and moderate-sized signaling molecules (e.g., ATP, glutamate). In the nervous system, activation of Panx1 channels has been extensively shown to contribute to distinct neurological disorders (epilepsy, chronic pain, migraine, neuroAIDS, etc.), but knowledge of the extent to which these channels have a physiological role remains restricted to three studies supporting their involvement in hippocampus dependent learning. Given that Panx1 channels may provide an important mechanism for activity-dependent neuron-glia interaction, we used Panx1 transgenic mice with global and cell-type specific deletions of Panx1 to interrogate their participation in working and reference memory. Using the eight-arm radial maze, we show that long-term spatial reference memory, but not spatial working memory, is deficient in Panx1-null mice and that both astrocyte and neuronal Panx1 contribute to the consolidation of long-term spatial memory. Field potential recordings in hippocampal slices of Panx1-null mice revealed an attenuation of both long-term potentiation (LTP) of synaptic strength and long-term depression (LTD) at Schaffer collateral-CA1 synapses without alterations of basal synaptic transmission or pre-synaptic paired-pulse facilitation. Our results implicate both neuronal and astrocyte Panx1 channels as critical players for the development and maintenance of long-term spatial reference memory in mice.

Keywords: long-term potentiation; pannexin; radial maze; spatial memory; synaptic plasticity.

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Conflict of interest statement

Price Obot is currently affiliated to Department of Emergency Medicine, Penn State Hershey Medical Center, Hershey, PA, USA.

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Locomotor activity and thigmotaxis are independent of Panx1. Median ± min/max values of the (A) total distance traveled and (B) time spent in the outer zone of the arena recorded from Panx1f/f (FF, black bars; n = 30), Panx1-null (KO, blue bars; n = 15), NFH-Cre:Panx1f/f (NFH, green bars; n = 14), and GFAP-Cre:Panx1f/f (GFAP, red bars; n = 23) mice exposed for 10 min to the open field.
Figure 2.
Figure 2.
Impaired long-term reference memory in mice lacking Panx1. (A, C, E, G) Mean ± sem of the (A) fraction of working memory correct errors (WM-C), (C) working memory incorrect errors (WM-I), (E) reference memory errors (RME), and (G) correct choices (correct arms) obtained during the training sessions. (B, D, F, H) Violin plots showing the median values of WM-C (B), WM-I (D), RME (F), correct arms (H) obtained during the test phase for Panx1f/f (FF, black symbols; n = 15), Panx1-null (KO, blue symbols; n = 21), NFH-Cre:Panx1f/f (NFH, green symbols; n = 12), and GFAP-Cre:Panx1f/f (GFAP, red symbols; n = 11) mice.
Figure 3.
Figure 3.
Basal synaptic transmission in Panx1-deficient mice. (A) Input–output (I/O) relations showing normalized fEPSP slopes at different stimulus intensities at CA3-CA1 synapses of hippocampal slices from control (WT) versus Panx1-null (Panx1 KO) mice. No significant difference in basal transmission was detected (two-way RM ANOVA: Fgenotype (1, 40) = 0.001400, p = 0.9703). (B) Paired-pulse facilitation ratio of the fEPSP at various inter-stimulus intervals. Significant difference was detected between WT and Panx1 KO mice but only at the 10 ms inter-pulse interval (p = 0.007; two-way RM ANOVA followed by Šidák's multiple comparison test). Insets: representative fEPSPs recorded from Panx1f/f (WT) and Panx1-null (KO) hippocampal slices in response to a stimulus intensity of 160 µA (in A) and to a 10 ms inter-pulse interval (in B). WT: n = 29 slices from eight male and eight female mice; KO: n = 13 slices from four male and three female mice.
Figure 4.
Figure 4.
Altered hippocampal synaptic plasticity in Panx1-deficient mice. (A-B) Time courses (A1, B1) and magnitudes (A2, B2) of long-term potentiation (LTP) and of long-term depression (LTD). LTP was elicited by theta burst (TBS) and LTD by low frequency (LFS) stimulation of hippocampal Schaffer collateral-CA1 synapses. Panx1-null mice (blue symbols, n = 17 slices from six male and six female mice) expressed significantly lower LTP compared to Panx1f/f mice (black symbols, n = 13 slices from five male and four female mice) (two tailled Student's t-test: t = 55.69, df = 20, p < 0.0001), and Panx1-null (blue symbols, n = 15 slices from six male and six female mice) exhibited diminished LTD compared to Panx1f/f mice (black symbols, n = 12 slices from four male and four female mice) (two-tailled Student's t-test: t = 29.58, df = 20, p < 0.0001). Each data point was normalized to the averaged baseline and expressed as mean ± sem. The first set of vertical dashed lines indicate application of TBS and LFS, respectively, and the second set indicates the 50th–60th minutes post-stimulation period used for LTP and LTD analyses. Insets: fEPSPs from representative Panx1f/f (WT) and Panx1-null (KO) hippocampal slices before and after TBS for LTP (A top) and LFS for LTD (B top).
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