Objective Traumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll‐like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury. Methods Slice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury. Results The studies identify that TLR4 signaling in neurons augments dentate granule cell calcium‐permeable α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (CP‐AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls. Interpretation These findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post‐traumatic neuronal excitability. Moreover, the TLR4‐dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4‐mediated increase in CP‐AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497–515

Objective. Despite much effort, obesity remains a significant public health problem. One of the main contributing factors is patients' perception of their target ideal body weight. This study aimed to assess this perception. Methods. The study took place in an urban area, with the majority of participants in the study being Hispanic (65.7%) or African-American (28.0%). Patients presented to an outpatient clinic were surveyed regarding their ideal body weight and their ideal BMI calculated. Subsequently they were classified into different categories based on their actual measured BMI. Their responses for ideal BMI were compared. Results. In 254 surveys, mean measured BMI was 31.71 ± 8.01. Responses to ideal BMI had a range of 18.89–38.15 with a mean of 25.96 ± 3.25. Mean (±SD) ideal BMI for patients with a measured BMI of <18.5, 18.5–24.9, 25–29.9, and ≥30 was 20.14 ± 1.46, 23.11 ± 1.68, 25.69 ± 2.19, and 27.22 ± 3.31, respectively. These differences were highly significant (P < 0.001, ANOVA). Conclusions. Most patients had an inflated sense of their target ideal body weight. Patients with higher measured BMI had higher target numbers for their ideal BMI. Better education of patients is critical for obesity prevention programs.

Traumatic brain injury is a major risk factor for acquired epilepsies and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting acquired epilepsies. Here we identify that signaling through an innate immune receptor toll-like receptor 4 (TLR4), in neurons, augments calcium permeable AMPA currents in the hippocampal dentate gyrus after brain injury. Blocking TLR4 signaling in vivo early after brain injury reduced dentate network excitability and seizure susceptibility. TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls.However, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. TLR4 antagonists failed to reduce post-injury seizure susceptibility when treatment was delayed and was less efficacious when AMPA currents were transiently enhanced during TLR4 antagonist treatment. These data identify a direct immune receptor regulation of posttraumatic neuronal excitability which is independent of glia. Moreover, the results demonstrate a causal association between TLR4-dependent early increase in dentate excitability and epileptogenesis. The findings suggest that the mechanisms underlying the aberrant TLR4 mediated increase in CP-AMPA after injury could be identified and selectively targeted to prevent epileptogenesis after traumatic brain injury. IntroductionAcquired epilepsies that develop after brain insults such as trauma are particularly refractory to treatments yet are potentially preventable if the underlying mechanisms are identified and appropriately targeted (1-3). A wealth of preclinical and clinical studies predict that neuronal excitability and plasticity act alongside inflammatory processes contribute to epileptogenesis (3-9). However, whether neurophysiological and inflammatory responses to injury interact and the mechanisms underlying these interactions are not fully understood (10).Activation of the innate immune receptor toll-like receptor 4 (TLR4) by the its ligand HMGB1, released during neuronal damage, is thought to play a critical role in the inflammatory responses during seizures and after brain injury (6, 11). TLR4 is expressed in both neurons and glia (11,12).Glial TLR4 signaling has been proposed to underlie increases in neuronal excitability and excitotoxicity by activating glial cytokines which enhance neuronal NMDA currents (11,13,14).In contrast, we recently identified TLR4 expression and enhancement in hippocampal dentate neurons after experimental brain injury, but not in astrocytes or microglia (12). Curiously, TLR4 signaling enhanced AMPA, but not NMDA currents in dentate neurons after brain injury. These data raise the possibility that TLR4 signaling after brain injury does not engage the classical glial pathways (15), but instead acts through neuronal effectors that have not been elucidated (16,17).The ability of TLR...