Apamin Improves Prefrontal Nicotinic Impairment in Mouse Model of Alzheimer's Disease

Cereb Cortex. 2020 Mar 21;30(2):563-574. doi: 10.1093/cercor/bhz107.


Disruption of attention is an early and disabling symptom of Alzheimer's disease (AD). The underlying cellular mechanisms are poorly understood and treatment options for patients are limited. These early attention deficits are evident in the TgCRND8 mouse, a well-established murine model of AD that recapitulates several features of the disease. Here, we report severe impairment of the nicotinic receptor-mediated excitation of prefrontal attentional circuitry in TgCRND8 mice relative to wild-type littermate controls. We demonstrate that this impairment can be remedied by apamin, a bee venom neurotoxin peptide that acts as a selective antagonist to the SK family of calcium-sensitive potassium channels. We probe this seeming upregulation of calcium-sensitive inhibition and find that the attenuated nicotinic firing rates in TgCRND8 attention circuits are mediated neither by greater cellular calcium signals nor by elevated SK channel expression. Instead, we find that TgCRND8 mice show enhanced functional coupling of nicotinic calcium signals to inhibition. This SK-mediated inhibition exerts a powerful negative feedback on nicotinic excitation, dampening attention-relevant signaling in the TgCRND8 brain. These mechanistic findings identify a new cellular target involved in the modulation of attention and a novel therapeutic target for early attention deficits in AD.

Keywords: Alzheimer’s disease; SK2; SK3; apamin; calcium-activated potassium channels; electrophysiology; mouse; multiphoton calcium imaging; nicotinic acetylcholine receptors; prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / physiopathology*
  • Animals
  • Apamin / administration & dosage*
  • Disease Models, Animal
  • Female
  • Male
  • Membrane Potentials
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Prefrontal Cortex / physiology*
  • Pyramidal Cells / physiology*
  • Receptors, Nicotinic / physiology*
  • Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors


  • Receptors, Nicotinic
  • Small-Conductance Calcium-Activated Potassium Channels
  • Apamin