Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells

Abstract

Neuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long lasting inflammatory response in hippocampal microglia associated with a concomitant up-regulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic-AMP gated channel type 1 (HCN1) protein level while Kv4.2 channels were unaltered as assessed by western blot. Immunohistochemistry confirmed the HCN1 decrease in CA1 pyramidal neurons and showed that these changes were associated with a reduction of TRIP8b, an auxiliary subunit for HCN channels implicated in channel subcellular localization and trafficking. At the physiological level, this effect translated into a 50% decrease in HCN1-mediated currents (Ih) measured in the distal dendrites of hippocampal CA1 pyramidal cells. At the functional level, the band-pass filtering properties of dendrites in the theta frequency range (4-12 Hz) and their temporal summation properties were compromised. We conclude that neuroinflammation can independently trigger an acquired channelopathy in CA1 pyramidal cell dendrites that alters their integrative properties. By directly changing cellular function, this phenomenon may participate in the phenotypic expression of various brain diseases.

Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

“…The contribution of glial mediators to TLR4 regulation of neuronal excitability has been identified in earlier studies. 10,13,53 Our findings in neuronal cultures demonstrate that glial signals are not engaged in the TLR4 enhancement of CP-AMPAR currents, revealing neuronal TLR4 signaling in the CNS. Future studies are needed to address the molecular underpinnings of TLR4 signaling in CNS neurons as has been examined in peripheral neurons.…”

“…A wealth of preclinical and clinical studies predict that neuronal excitability and plasticity act alongside inflammatory processes and contribute to epileptogenesis . However, the interaction between neurophysiological and inflammatory responses to injury and the underlying mechanisms are not fully understood . Activation of the innate immune receptor Toll‐like receptor 4 (TLR4) by its ligand high mobility group box chromosomal protein 1 (HMGB1), which is released during neuronal damage, is thought to play a critical role in the inflammatory responses to seizures and brain injury .…”

“…[3][4][5][6][7][8][9] However, the interaction between neurophysiological and inflammatory responses to injury and the underlying mechanisms are not fully understood. 10 Activation of the innate immune receptor Toll-like receptor 4 (TLR4) by its ligand high mobility group box chromosomal protein 1 (HMGB1), which is released during neuronal damage, is thought to play a critical role in the inflammatory responses to seizures and brain injury. 6,11 TLR4 is expressed in both neurons and glia.…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…Additional mechanisms of hyperexcitability mediated by the IL‐1R1/TLR4 signaling pathway include the downregulation of the HCN1 channel and the related Ih current on dendrites of hippocampal pyramidal neurons, as assessed in rats upon intraventricular LPS injection. Activation of the IL‐1R/TLR4 signaling pathway reduces both levels and function of HCN1 channels . These channels are important regulators of the filtering properties of hippocampal pyramidal cell dendrites, their responses to excitatory inputs, and they are involved in theta rhythms, which have been linked to cognitive functions.…”

“…Activation of the IL-1R/TLR4 signaling pathway reduces both levels and function of HCN1 channels. 127 These channels are important regulators of the filtering properties of hippocampal pyramidal cell dendrites, their responses to excitatory inputs, and they are involved in theta rhythms, which have been linked to cognitive functions. These channels are downregulated in experimental and human epilepsy tissue, and contribute to seizures.…”