Trigeminal nerve activation in response to inflammatory stimuli has been shown to increase neuron–glia communication via gap junctions in trigeminal ganglion. The goal of this study was to identify changes in the expression of gap junction proteins, connexins (Cxs), in trigeminal ganglia in response to acute or chronic joint inflammation. Although mRNA for Cxs 26, 36, 40 and 43 was detected under basal conditions, protein expression of only Cxs 26, 36 and 40 increased following capsaicin or complete Freund’s adjuvant (CFA) injection into the temporomandibular joint (TMJ). While Cx26 plaque formation between neurons and satellite glia was transiently increased following capsaicin injections, Cx26 plaque formation between neurons and satellite glia was sustained in response to CFA. Interestingly, levels of Cx36 and Cx40 were only elevated in neurons following capsaicin or CFA injections, but the temporal response was similar to that observed for Cx26. In contrast, Cx43 expression was not increased in neurons or satellite glial cells in response to CFA or capsaicin. Thus, trigeminal ganglion neurons and satellite glia can differentially regulate Cx expression in response to the type and duration of inflammatory stimuli, which likely facilitates increased neuron–glia communication during acute and chronic inflammation and pain in the TMJ.

Background Sensitization and activation of trigeminal neurons are implicated in the underlying pathology of migraine, acute sinusitis, and allergic rhinitis. Cell bodies of trigeminal neurons that provide sensory innervation of the dura and nasal mucosa reside in the trigeminal ganglion in association with satellite glial cells where they communicate via gap junctions. Gap junctions, channels formed by connexins, modulate the excitability state of both neurons and glia under pathological conditions. Tonabersat, a compound being tested as an antimigraine drug, is thought to block gap junction activity. Objective To investigate the cellular events within trigeminal ganglia that may account for the significant comorbidity of migraine and rhinosinusitis and determine the effect of tonabersat on neuron-satellite glia communication. Methods Sprague Dawley rats injected with True Blue were used to localize neuronal cell bodies in the ganglion and study neuronglia signaling via gap junctions in the trigeminal ganglion. Dye coupling studies were conducted under basal conditions and in response to tumor necrosis factor-alpha injection into the whisker pad and/or capsaicin injection into the eyebrow. Changes in connexin 26 and active p38 levels were determined by immunohistochemistry. In addition, the effect of tonabersat prior to chemical stimulation on gap junction activity and expression of connexins and active p38 was investigated. Results Injection of tumor necrosis factor-alpha, a cytokine implicated in the pathology of acute sinusitis and allergic rhinitis, into the V2 region was shown to lower the amount of capsaicin required to stimulate neurons located in the V1 region of the ganglion. While injection of tumor necrosis factor-alpha into the whisker pad or capsaicin injection into the eyebrow alone did not cause increased dye movement, the combination of both stimuli greatly increased neuron-satellite glia communication via gap junctions in both V1 and V2 regions. The change in gap junction activity was accompanied by increased expression of connexin 26 and active p38 levels in both neurons and satellite glia in V1 and V2 regions. Pretreatment with tonabersat inhibited gap junction communication between neurons and satellite glia and blocked the increase in connexin 26 and active p38 levels in response to injection of both tumor necrosis factor-alpha (V2) and capsaicin (V1). Conclusions We propose that increased levels of tumor necrosis factor-alpha, as reported during acute sinusitis and allergic rhinitis, reduces the amount of capsaicin necessary to stimulate V1 neurons that leads to cellular changes in both V1 and V2 regions. The cellular events observed in this study may help to explain, in part, the significant comorbidity reported with migraine and rhinosinusitis. In addition, we have provided evidence to suggest that tonabersat can prevent increased neuron-satellite glia signaling and, thus, may be useful in the treatment of migraine, acute sinusitis, and allergic rhinitis.

TAR-DNA binding protein-43 (TDP-43) proteinopathy is seen in multiple brain diseases. A standardized terminology was recommended recently for common age-related TDP-43 proteinopathy: limbic-predominant, age-related TDP-43 encephalopathy (LATE) and the underlying neuropathological changes, LATE-NC. LATE-NC may be co-morbid with Alzheimer’s disease neuropathological changes (ADNC). However, there currently are ill-defined diagnostic classification issues among LATE-NC, ADNC, and frontotemporal lobar degeneration with TDP-43 (FTLD-TDP). A practical challenge is that different autopsy cohorts are composed of disparate groups of research volunteers: hospital- and clinic-based cohorts are enriched for FTLD-TDP cases, whereas community-based cohorts have more LATE-NC cases. Neuropathological methods also differ across laboratories. Here, we combined both cases and neuropathologists’ diagnoses from two research centres—University of Pennsylvania and University of Kentucky. The study was designed to compare neuropathological findings between FTLD-TDP and pathologically severe LATE-NC. First, cases were selected from the University of Pennsylvania with pathological diagnoses of either FTLD-TDP (n = 33) or severe LATE-NC (mostly stage 3) with co-morbid ADNC (n = 30). Sections from these University of Pennsylvania cases were cut from amygdala, anterior cingulate, superior/mid-temporal, and middle frontal gyrus. These sections were stained for phospho-TDP-43 immunohistochemically and evaluated independently by two University of Kentucky neuropathologists blinded to case data. A simple set of criteria hypothesized to differentiate FTLD-TDP from LATE-NC was generated based on density of TDP-43 immunoreactive neuronal cytoplasmic inclusions in the neocortical regions. Criteria-based sensitivity and specificity of differentiating severe LATE-NC from FTLD-TDP cases with blind evaluation was ∼90%. Another proposed neuropathological feature related to TDP-43 proteinopathy in aged individuals is ‘Alpha’ versus ‘Beta’ in amygdala. Alpha and Beta status was diagnosed by neuropathologists from both universities (n = 5 raters). There was poor inter-rater reliability of Alpha/Beta classification (mean κ = 0.31). We next tested a separate cohort of cases from University of Kentucky with either FTLD-TDP (n = 8) or with relatively ‘pure’ severe LATE-NC (lacking intermediate or severe ADNC; n = 14). The simple criteria were applied by neuropathologists blinded to the prior diagnoses at University of Pennsylvania. Again, the criteria for differentiating LATE-NC from FTLD-TDP was effective, with sensitivity and specificity ∼90%. If more representative cases from each cohort (including less severe TDP-43 proteinopathy) had been included, the overall accuracy for identifying LATE-NC was estimated at >98% for both cohorts. Also across both cohorts, cases with FTLD-TDP died younger than those with LATE-NC (P < 0.0001). We conclude that in most cases, severe LATE-NC and FTLD-TDP can be differentiated by applying simple neuropathological criteria.

Cell bodies of trigeminal nerves, which are located in the trigeminal ganglion, are completely surrounded by satellite glial cells and together form a functional unit that regulates neuronal excitability. The goals of this study were to investigate the cellular organization of the rat trigeminal ganglia during postnatal development and correlate those findings with expression of proteins implicated in neuron–glia interactions. During postnatal development there was an increase in the volume of the neuronal cell body, which correlated with a steady increase in the number of glial cells associated with an individual neuron from an average of 2.16 at birth to 7.35 on day 56 in young adults. Interestingly, while the levels of the inwardly rectifying K+ channel Kir4.1 were barely detectable during the first week, its expression in satellite glial cells increased by day 9 and correlated with initial formation of functional units. Similarly, expression of the vesicle docking protein SNAP-25 and neuropeptide calcitonin gene-related peptide was readily detected beginning on day 9 and remained elevated throughout postnatal development. Based on our findings, we propose that the expression of proteins involved in facilitating neuron–glia interactions temporally correlates with the formation of mature functional units during postnatal development of trigeminal ganglion.

Pain in the head and face, which can be very severe and debilitating, often involves activation of trigeminal ganglion nerves. The craniofacial symptoms can manifest as acute or transient conditions such as toothaches and headaches, or can transform into more chronic conditions such as migraine, rhinosinusitis, temporomandibular joint (TMJ) disorder, or trigeminal neuralgia. Traditionally, it is known that peripheral tissue injury or inflammation leads to excitation of trigeminal nerves that release inflammatory molecules in the periphery as well as facilitate transmission of nociceptive signals to the central nervous system. However, findings from recent studies have demonstrated that peripheral tissue injury or inflammation also leads to increased interactions between neuronal cell bodies and satellite glial cells within the trigeminal ganglion. These cell-to-cell interactions, which involve the transfer of key regulatory mediators via channels or gap junctions as well as paracrine signaling, are thought to play an important role in the induction and maintenance of peripheral sensitization of trigeminal nociceptors. The focus of this review will be on understanding the importance of the increased signaling between neuronal cell bodies and satellite glia cells in trigeminal ganglia to the development of persistent pain.Keywords: Trigeminal, neuron, satellite glia, signaling, gap junctions -connexins, neuropathic, inflammation, acute, chronic, peripheral sensitization, comorbitity, migraine, TMJ, rhinosinusitus. TRIGEMINAL NERVESPain in the head and face can be very severe and debilitating. In fact, the head and face represent some of the most common pain sites in the body [1][2][3]. These craniofacial symptoms can manifest as acute or transient conditions such as toothaches and headaches, or can transform into more chronic conditions such as migraine, rhinosinusitis, temporomandibular joint (TMJ) disorder or trigeminal neuralgia. While physiological pain is typically of short duration and facilitates an appropriate response to noxious stimuli, pathological pain is persistent, does not have longterm benefits to the organism and can lead to tissue damage and hence is maladaptive. Chronic diseases involving the head and face often involve activation of trigeminal ganglion nerves. The trigeminal nerve consists of three major branches that provide somatosensory innervation of distinct regions of the head, face, as well as nasal, sinus, and oral cavities [4]. Activation of a particular branch can be caused by peripheral tissue injury or compression of the nerve processes resulting in neuroinflammation or caused by tissue inflammation mediated by release of pro-inflammatory molecules at site of injury initiating a neurogenic inflammatory response. Following activation, trigeminal nerves release neuropeptides and other inflammatory molecules from peripheral terminals that initiate and maintain neurogenic inflammation, which is characterized by vasodilation, protein plasma leakage, mast cell activation, *Addre...