The Molecular Basis for the Calcium-Dependent Slow Afterhyperpolarization in CA1 Hippocampal Pyramidal Neurons

Abstract

Neuronal signal transmission depends on the frequency, pattern, and timing of spike output, each of which are shaped by spike afterhyperpolarizations (AHPs). There are classically three post-spike AHPs of increasing duration categorized as fast, medium and slow AHPs that hyperpolarize a cell over a range of 10 ms to 30 s. Intensive early work on CA1 hippocampal pyramidal cells revealed that all three AHPs incorporate activation of calcium-gated potassium channels. The ionic basis for a fAHP was rapidly attributed to the actions of big conductance (BK) and the mAHP to small conductance (SK) or Kv7 potassium channels. In stark contrast, the ionic basis for a prominent slow AHP of up to 30 s duration remained an enigma for over 30 years. Recent advances in pharmacological, molecular, and imaging tools have uncovered the expression of a calcium-gated intermediate conductance potassium channel (IK, KCa3.1) in central neurons that proves to contribute to the slow AHP in CA1 hippocampal pyramidal cells. Together the data show that the sAHP arises in part from a core tripartite complex between Cav1.3 (L-type) calcium channels, ryanodine receptors, and IK channels at endoplasmic reticulum-plasma membrane junctions. Work on the sAHP in CA1 pyramidal neurons has again quickened pace, with identified contributions by both IK channels and the Na-K pump providing answers to several mysteries in the pharmacological properties of the sAHP.

Behavior of KCNQ Channels in Neural Plasticity and Motor Disorders

“…The morphological formation of these neurons within the hippocampus leads to the further subfield classification of pyramidal cells in what is known as Cornu Ammonus (CA), divided into CA1, CA2, and CA3 [ 49 , 50 ]. These regions serve an important role in localizing KCNQ channel function in synaptic plasticity [ 49 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. Within synaptic plasticity, two major models involved in the application of neural plasticity are long-term potentiation (LTP) and long-term depression (LTD) [ 59 ].…”

“…Historically, LTP was initially found in animal models, which found a sustained enhancement in the hippocampus following high-frequency electrode stimulation. LTD was later recognized after laboratory models found the opposite effect following low-frequency simulations [ 61 , 62 , 63 , 64 , 65 ]. At the cellular level, the literature suggests there are numerous factors that play a role in creating the genres of synaptic efficiency and, ultimately, neural plasticity [ 63 , 64 , 65 , 66 , 67 , 68 ].…”

Age‐related deficits in neuronal physiology and cognitive function are recapitulated in young mice overexpressing the L‐type calcium channel, CaV1.3

“…An even longer‐lasting part of the AHP (the slow AHP [sAHP]) is mediated by an apamin‐insensitive current, which has a slower rise time and lasts for several seconds. The exact identity of the channel (or channels) underlying this current remains somewhat controversial (Sahu & Turner, 2021), but it has a clear calcium dependence as pharmacological or genetic interventions that alter calcium levels strongly modulate its activity and, consequently, the size of the sAHP (Gamelli et al, 2011; McKinney et al, 2009). Thus, an age‐related increase in [Ca 2+ ] i is a likely driver of the age‐related increase in the sAHP via amplification of this underlying Ca 2+ ‐activated K + current.…”

Sevoflurane exposure causes neuronal apoptosis and cognitive dysfunction by inducing ER stress via activation of the inositol 1, 4, 5-trisphosphate receptor

“…As a major intracellular messenger, calcium is involved in regulating the physiological activities of many cells and tissues, including muscle contraction, metabolism and cell division. In the resting physiological state, calcium ions are maintained at relatively high concentrations outside the cell and low concentrations inside the cell through homeostatic flux ( Kumar, 2020 ; Sahu and Turner, 2021 ). When cells are stimulated, this calcium homeostasis is broken, and cytoplasmic calcium ([Ca 2+ ]c) levels increase instantaneously, inducing cell damage or death, such as apoptosis and necroptosis under certain circumstances ( Cheng et al, 2022 ; Matuz-Mares et al, 2022 ).…”