Abstract Body: INTRODUCTION: Post-Stroke Cognitive Impairment (PSCI) is increasingly recognized as a major factor in long-term disability. Therefore, new therapies that enhance post-stroke brain function (plasticity) are appealing in translational research. Activation of the cation channel TRPM2 after middle cerebral artery occlusion (MCAO) induces PSCI-like symptoms, such as memory impairment and deficits in Long-Term Potentiation (LTP). Determining the mediator of chronic TRPM2 channel activation may implicate a novel contributor to LTP deficit. The enzyme CD38 may be this mediator, as it produces the TRPM2 activator ADPr. Here, we investigate astrocytic CD38’s role in MCAO and TRPM2-induced deficits.
METHODS: LTP was assessed through Extracellular Field Recordings from CA3-CA1 synapses of Acute Hippocampal Slices. Immunofluorescence stained for GFAP and CD38 in hippocampal sections. Wt or CD38^-/- mice were subjected to 60-minute MCAO, or Sham, and assessed for LTP 7 days later. Wt or TRPM2^-/- mice received Intracranial Administration (200nL, 10¹² gc/mL) of AAV-CD38-eGFP (astrocyte CD38 overexpression) or AAV-eGFP (control) to the right ventral CA1 and assessed for LTP after 21 days. All mice were 8-12-week-old males. Differences between groups were determined with either Welch’s T-Test or One-Way ANOVA followed by post-hoc test.
RESULTS: We observed increased expression of CD38, colocalized with GFAP (astrocyte marker), in the hippocampus 7 days post-MCAO. Sham Wt mice exhibited robust LTP, not observed in Wt MCAO (Wt-Sham: 176% +/- 33.9 vs Wt-MCAO: 135% +/- 23, p < 0.05). Conversely, CD38^-/- mice displayed robust LTP after either Sham or MCAO, depicting protection of synaptic plasticity (CD38^-/--Sham: 175.2% +/- 24.1, CD38^-/--MCAO: 184.8% +/- 27.3). AAV-CD38-eGFP astrocytic overexpression vector produced impairment in LTP in the Wt mice compared to the empty vector control (Wt-eGFP: 195.6% +/- 46 vs Wt-CD38:141.5% +/- 38.7, p < 0.05). No differences were observed in TRPM2^-/- mice injected with either virus. (TRPM2^-/- -eGFP: 180.3% +/- 39.4, TRPM2^-/--CD38 174% +/- 54.1)
CONCLUSIONS: Our study implicates astrocytic CD38 as a novel inducer of hippocampal synaptic plasticity impairment. CD38 is increased following injury and required for MCAO-induced LTP deficit. Additionally, overexpression is sufficient to impair LTP in uninjured mice, in a TRPM2-dependent manner. Astrocytic CD38 is a novel target for PSCI and the likely upstream mediator of chronic TRPM2 activation.