Neuroplasticity elicited by peripheral immune challenge with a viral mimetic

Peripheral viral infections are well known to profoundly alter brain function; however detailed mechanisms of this immune-to-brain communication have not been deciphered. This review focuses on studies of cerebral effects of peripheral viral challenge employing intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). In this paradigm, PIC challenge induces the acute phase response (APR) characterized by a transient surge of circulating inflammatory factors, primarily IFNβ, IL-6 and CXCL10. The blood-borne factors, in turn, elicit the generation of CXCL10 by hippocampal neurons. Neurons also express the cognate receptor of CXCL10, i.e., CXCR3 implicating the existence of autocrine/paracrine signaling. The CXCL10/CXCR3 axis mediates the ensuing neuroplastic changes manifested as neuronal hyperexcitability, seizure hypersusceptibility, and sickness behavior. Electrophysiological studies revealed that the neuroplastic changes entail the potentiation of excitatory synapses likely at both pre- and postsynaptic loci. Excitatory synaptic transmission is further augmented by PIC challenge-induced elevation of extracellular glutamate that is mediated by astrocytes. In addition, the hyperexcitability of neuronal circuits might involve the repression of inhibitory signaling. Accordingly, CXCL10 released by neurons activates microglia whose processes invade perisomatic inhibitory synapses, resulting in a partial detachment of the presynaptic terminals, and thus, de-inhibition. This process might be facilitated by the cerebral complement system, which is also upregulated and activated by PIC challenge. Moreover, CXCL10 stimulates the expression of neuronal c-fos protein, another index of hyperexcitability. The reviewed studies form a foundation for full elucidation of the fascinating intersection between peripheral viral infections and neuroplasticity. Because the activation of such pathways may constitute a serious comorbidity factor for neuropathological conditions, this research would advance the development of preventive strategies.