Presynaptic L-Type Ca²⁺ Channels Increase Glutamate Release Probability and Excitatory Strength in the Hippocampus during Chronic Neuroinflammation

Abstract

Neuroinflammation is involved in the pathogenesis of several neurologic disorders, including epilepsy. Both changes in the input/output functions of synaptic circuits and cell Ca 21 dysregulation participate in neuroinflammation, but their impact on neuron function in epilepsy is still poorly understood. Lipopolysaccharide (LPS), a toxic byproduct of bacterial lysis, has been extensively used to stimulate inflammatory responses both in vivo and in vitro. LPS stimulates Toll-like receptor 4, an important mediator of the brain innate immune response that contributes to neuroinflammation processes. Although we report that Toll-like receptor 4 is expressed in both excitatory and inhibitory mouse hippocampal neurons (both sexes), its chronic stimulation by LPS induces a selective increase in the excitatory synaptic strength, characterized by enhanced synchronous and asynchronous glutamate release mechanisms. This effect is accompanied by a change in short-term plasticity with decreased facilitation, decreased post-tetanic potentiation, and increased depression. Quantal analysis demonstrated that the effects of LPS on excitatory transmission are attributable to an increase in the probability of release associated with an overall increased expression of L-type voltage-gated Ca 21 channels that, at presynaptic terminals, abnormally contributes to evoked glutamate release. Overall, these changes contribute to the excitatory/inhibitory imbalance that scales up neuronal network activity under inflammatory conditions. These results provide new molecular clues for treating hyperexcitability of hippocampal circuits associated with neuroinflammation in epilepsy and other neurologic disorders.

Synaptamide Improves Cognitive Functions and Neuronal Plasticity in Neuropathic Pain

“…We assume that synaptamide inhibits the hippocampal neurons’ hyperactivation and prevents the dendritic tree structure disruption, by suppressing the microglial activity and the production of the proinflammatory cytokines. Suppression of neuroinflammation processes leads to the stabilization of the neurotransmitters release, expression of excitatory and inhibitory receptors [ 76 ], as well as the dendritic spines’ density and configuration [ 77 ]. Together, these properties have a beneficial effect on the hippocampal functional state, including synaptic transmission and hippocampus-dependent cognitive processes.…”

PRRT2 modulates presynaptic Ca2+ influx by interacting with P/Q-type channels

“…The above results suggest that PRRT2 deficiency may reduce excitatory strength through a negative modulation of presynaptic VGCCs coupled with SV fusion. N- and P/Q-type VGCCs are the main actors mediating Ca 2+ -triggered glutamate release at the active zones of central synapses, while L-type channels do not significantly contribute to glutamatergic transmission under physiological conditions ( Giansante et al., 2020 ; Nanou and Catterall, 2018 ; Reid et al., 1997 ; Takahashi and Momiyama, 1993 ).…”

A “Drug-Dependent” Immune System Can Compromise Protection against Infection: The Relationships between Psychostimulants and HIV

“…However, TLR4 and TLR2 expression by neurons was later described, as was their modulation by IFN-γ, similar to that in immune cells [ 176 , 180 , 181 ]. Hippocampal TLR4 signaling participates in neuroinflammatory responses associated with traumatic brain injury [ 182 ], seizures [ 183 ], imbalances in excitatory/inhibitory strength [ 180 ] and long-term potentiation, defects that affect hippocampal memory [ 184 , 185 ]. TLRs have also been shown to participate in neurogenesis and neuronal differentiation, and a growing body of evidence implicates these receptors in other CNS mechanisms [ 186 ].…”

“…TLR expression among resident CNS cells was first studied in microglia (an innate immune cell) and astrocytes, with neurons only considered targets of glial factors released after TLR stimulation [178,179]. However, TLR4 and TLR2 expression by neurons was later described, as was their modulation by IFN-γ, similar to that in immune cells [176,180,181]. Hippocampal TLR4 signaling participates in neuroinflammatory responses associated with traumatic brain injury [182], seizures [183], imbalances in excitatory/inhibitory strength [180] and long-term potentiation, defects that affect hippocampal memory [184,185].…”