Synaptoimmunology - roles in health and disease

Abstract

Mounting evidence suggests that the nervous and immune systems are intricately linked. Many proteins first identified in the immune system have since been detected at synapses, playing different roles in normal and pathological situations. In addition, novel immunological functions are emerging for proteins typically expressed at synapses. Under normal conditions, release of inflammatory mediators generally represents an adaptive and regulated response of the brain to immune signals. On the other hand, when immune challenge becomes prolonged and/or uncontrolled, the consequent inflammatory response leads to maladaptive synaptic plasticity and brain disorders. In this review, we will first provide a summary of the cell signaling pathways in neurons and immune cells. We will then examine how immunological mechanisms might influence synaptic function, and in particular synaptic plasticity, in the healthy and pathological CNS. A better understanding of neuro-immune system interactions in brain circuitries relevant to neuropsychiatric and neurological disorders should provide specific biomarkers to measure the status of the neuroimmunological response and help design novel neuroimmune-targeted therapeutics.

Keywords: Immune system; Microglia; Nervous system; Neuroinflammation; Synaptic plasticity.

Fig. 1

Some of the main signaling pathways in LTP and LTD. LTP involves (at different synapses) several type of receptors which include NMDA receptor (GluN), voltage dependent calcium channel (VDCC), neurotrophin receptor (trkB), adenosine 2 receptor (A2R) or dopamine receptor (DAR). These receptors activate intracellular signaling pathways with local and/or somatic effects, such as phosphoinositide-3 kinase (PI3K)/Akt, protein kinase A (PKA)/ mitogen activated protein kinases (MAPK), calpain/ striatal enriched protein tyrosine phosphatase (STEP) and calcium calmodulin kinase II (CaMKII) pathways. LTD can be triggered by the activation of, for example, GluN, VDCC and metabotropic glutamate receptors (mGlu), depending of the form of LTD. Calcineurin (PP2B)/protein phosphatase 1 (PP1) associated to Janus kinase 2 (JAK2)/ signal transducers and activators of transcription 3 (STAT3), PI3K/Akt and glycogen synthase kinase 3 (GSK3) are mainly required for GluN dependent LTD whereas mGlu dependent LTD activates mainly phospholipase C (PLC)/Protein Kinase C (PKC) and eukaryotic elongation factor 2 kinase (eEF2K) signaling pathways. Sequence of activation of these pathways and inter-regulation between them are two key features to obtain synaptic plasticity events

Figu. 2

A schematic of a synapse showing pre, post elements, astrocytes and microglia. Brain and immune cells undergo a dynamic dialog. Peripheral immune cells, such as T-lymphocytes, macrophages and dendritic cells, coming from the cerebrospinal fluid or carried by blood vessels penetrate the brain through the blood brain barrier. They either have a surveilling activity or are attracted by the chemokines released by injured tissues. Microglia, the brain resident immune cells, perform a constant surveilling activity and are in particular attracted by synapse activity, locus of an intense interplay between neurons and glial cells. Many neurotransmitters circulate between these cell types resulting in the modulation of the synaptic functions. Increasing evidence suggest that molecules and signaling pathways first discovered for the immune system takes an important place in the physiological functioning of the synapse. Growth factor receptor (GF-R); Glutamate (Glu); Gamma Amino Butyric Acid (GABA); Acetylcholine (Ach); Dopamine (DA), Serotonin (5-HT), Adenosine tri-phosphate (ATP). (top scheme, cerebral structure inspired from [37])

Fig. 3

Signaling pathways in inflammation / immune response and how genetic risk factors for (e.g. AD) may impact via these pathways. Oligomeric or aggregate of amyloid beta peptides (Aβ), as occurring during Alzheimer’s disease, are detected by pattern recognition receptor (PRR) like Toll like receptors. In microglia they stimulate the production and release of cytokines such as interleukins (IL). These interleukins are detected by astrocytes and neurons, where they stimulate signaling pathways that interfere directly with the signaling pathways activated during synaptic plasticity, inducing deficits in LTP or exacerbated LTD. Aβ peptides can also interfere directly with neurotransmitter receptors (Glutamate receptors (GluN, mGlu) or acetylcholine receptors) leading to abnormal neurotransmission. (top scheme, cerebral structure inspired from [37])