Scavuzzo 2019 J Neurophysiol
|Scavuzzo CJ, Leblancq MJ, Nargang F, Lemieux H, Hamilton TJ, Dickson CT (2019) The amnestic agent anisomycin disrupts intrinsic membrane properties of hippocampal neurons via a loss of cellular energetics. J Neurophysiol [Epub ahead of print].|
Abstract: The nearly axiomatic idea that de novo protein synthesis is necessary for long term memory consolidation is based heavily on behavioural studies using translational inhibitors such as anisomycin (ANI). Although inhibiting protein synthesis has been shown to disrupt the expression of memory, translational inhibitors have also been found to profoundly disrupt basic neurobiological functions, including the suppression of ongoing neural activity in vivo. Here, using transverse hippocampal brain slices, we monitored the passive and active membrane properties of hippocampal CA1 pyramidal neurons using intracellular whole cell recordings during a brief ~30 minute exposure to fast-bath-perfused ANI. ANI suppressed protein synthesis to 46% of control levels as measured using incorporation of radio-labeled amino acids and autoradiography. During its application, ANI caused a significant depolarization of the membrane potential, without any changes in apparent input resistance or membrane time constant. ANI-treated neurons also showed significant decreases in firing frequencies, spike amplitudes, and showed increases in spike width across spike trains, without changes in spike threshold. As these changes indicated a loss of cellular energetics contributing to maintenance of ionic gradients across the membrane, we confirmed that ANI impaired mitochondrial function by reduced staining with 2,3,5-triphenyltetrazolium chloride (TTC), and also impaired cytochrome c oxidase (Complex IV) activity as indicated through high-resolution respirometry. These findings emphasize that ANI-induced alterations in neural activity and metabolism are a likely consequence of cell-wide translational inhibition. Critical re-evaluation of studies using translational inhibitors to promote the protein synthesis dependent idea of long-term memory is absolutely necessary.
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Rat Tissue;cell: Nervous system Preparation: Homogenate
Coupling state: LEAK, OXPHOS Pathway: N, S, CIV, NS, ROX HRR: Oxygraph-2k