T-Cell Receptor Activation Decreases Excitability of Cortical Interneurons by Inhibiting α7 Nicotinic Receptors

Abstract

Many proteins in the immune system are also expressed in the brain. One such class of immune proteins are T-cell receptors (TCRs), whose functions in T lymphocytes in adaptive immunity are well characterized. In the brain, TCRs are confined to neocortical neurons, but their functional role has not been determined. In mouse layer 1 neocortical neurons, TCR activation inhibited ␣7 nicotinic currents. TCRs modulated ␣7 currents via tyrosine phosphorylation of ␣7 nicotinic receptors (nAChRs) through src tyrosine kinases because eliminating lck kinase expression, coexpressing fyn kinase dead, or mutating tyrosine to alanine in ␣7 blocked the effect of TCR activation. We found that TCR stimulation decreased surface ␣7 nAChRs and reduced single-channel conductance. These results reveal that TCRs play a major role in the modulation of cholinergic neurotransmission in the brain mediated by ␣7 nAChRs and that this has a profound effect on regulating neuronal excitability.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…Effects of genistein or specific Src-family kinase inhibitors were observed both on reconstituted a7 nAChRs expressed in Xenopus oocytes or cell lines as well as on native receptors and confirmed that activity of a7 nAChRs can be modulated by phosphorylation (Charpantier et al, 2005). More recent experiments confirmed the relevance of T cell receptors in the phosphorylation and modulation of a7 nAChRs in the brain (Komal et al, 2014). Activation of T cell receptors, expressed in neocortical neurons, Fig.…”

T-cell receptors modify neuronal function in the central nervous system

“…Our lab has shown that activation of TCRs decreases neuronal excitability of layer 1 interneurons of the prefrontal cortex through attenuation of a7 nAChR activity [9]. This TCR mediated partial brake on a7 nAChR activity is conveyed by endogenous basal activation of TCRs in the CNS as neurons recorded from TCRb knockout mice had significantly larger a7 nicotinic currents than neurons recorded from wildtype mice.…”

“…Furthermore, intercellular signaling mediated via receptor tyrosine kinases such as insulin receptors [31,32], which bind to released insulin, and TrkB receptors [33,34], which bind to released brain-derived neurotrophic factor, negatively modulates a7 nAChR currents similar to the actions of TCRs [9]. This begs the question why would neurons need this extra redundancy of another membrane receptor, namely the TCR, that ultimately signals through tyrosine kinases?…”

“…Whether the MHC I mediated reduction of excitatory synapses is mediated by microglia is yet unproven. Similarly, TCRs function to reduce a7 nAChR activity in CNS neurons [9]. However, it is not yet determined whether TCR activation results in a reduction in the number of cholinergic synapses as its glutamatergic counterpart.…”

“…However, more recent studies have shown that proteins, previously thought to be expressed solely in the immune system, are also expressed in the CNS and convey neuronal function [2,3]. Shatz et al [4][5][6][7][8] and others [9] have demonstrated the expression of a number of immune proteins in the brain with unique neuronal functions. One such class of immune proteins in the CNS are T-cell receptor proteins and another are major histocompatibility complex (MHC) molecules.…”