Presynaptic L-type Ca2+ channels increase glutamate release probability and excitatory strength in the hippocampus during chronic neuroinflammation.

Neuroinflammation is involved in the pathogenesis of several neurological disorders, including epilepsy. Both changes in the input/output functions of synaptic circuits and cell Ca2+ dysregulation participate in neuroinflammation, but their impact on neuron function in epilepsy is still poorly understood. Lipopolysaccharide (LPS), a toxic by-product of bacterial lysis, has been extensively used to stimulate inflammatory responses both in vivo and in vitro LPS stimulates Toll-like receptor 4 (TLR4), an important mediator of the brain innate immune response that contributes to neuroinflammation processes. Although we report that TLR4 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 Ca2+ 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 neurological disorders.SIGNIFICANCE STATEMENTNeuroinflammation is thought to have a pathogenetic role in epilepsy, a disorder characterized by an imbalance between excitation/inhibition. Fine-adjustment of network excitability and regulation of synaptic strength are both implicated in the homeostatic maintenance of physiological levels of neuronal activity. Here, we focused on the effects of chronic neuroinflammation induced by Lipopolysaccharides on hippocampal glutamatergic and GABAergic synaptic transmission. Our results show that, upon chronic stimulation with Lipopolysaccharides, glutamatergic, but not GABAergic, neurons exhibit an enhanced synaptic strength and changes in short-term plasticity due to an increased glutamate release that results from an anomalous contribution of L-type Ca2+ channels to neurotransmitter release.