Electrophysiological measures and using a machine learning classification algorithm collectively suggest that pharmacological inhibitors targeting both monoacylglycerol lipase and fatty acid amide hydrolase (e

Electrophysiological measures and using a machine learning classification algorithm collectively suggest that pharmacological inhibitors targeting both monoacylglycerol lipase and fatty acid amide hydrolase (e.g., JZL195) may SIS3 be most efficacious in SIS3 attenuating TBI-induced neuronal dysfunction at site of injury. and and are examined, the accuracy index is (% of correctly classified + % of correctly classified)/(total no. spike threshold, spiking responses to current input, voltage sag (rebound response to hyperpolarization-activated inward current), and burst firing. We also measured the frequency and amplitude of spontaneous excitatory postsynaptic currents. We then used the aggregate parameter sets (intrinsic + synaptic properties) to apply a machine learning classification algorithm to quantitatively compare neural population responses from each experimental group. Collectively, our electrophysiological and computational results indicate that sham neurons are the most distinguishable from TBI neurons. Administration of EC degradation inhibitors post-TBI exerted varying degrees of rescue, approximating the neuronal phenotype of sham neurons, with neurons from TBI/JZL195 (a dual MAGL/FAAH inhibitor) being most similar to neurons from sham rats. NEW & NOTEWORTHY This study elucidates neuronal properties altered by traumatic brain injury (TBI) in layer 5 of sensorimotor cortex, which may be implicated in post-TBI circuit dysfunction. We compared effects of systemic administration of four different endocannabinoid degradation inhibitors within a clinically relevant window postinjury. Electrophysiological measures and using a machine learning classification algorithm collectively suggest that pharmacological inhibitors targeting both monoacylglycerol lipase and fatty acid amide hydrolase (e.g., JZL195) may be most efficacious in attenuating TBI-induced neuronal dysfunction at site of injury. and and are examined, the accuracy index is usually (% of correctly classified + % of correctly classified)/(total no. in + total no. in 0.05. RESULTS Synaptic Properties Following TBI and Administration of EC Degradation Inhibitors Physique 2, and = 0.002; Fig. 2 0.01), TBI/Veh vs. TBI/JZL184 (19.0??2.0 pA, 0.05), TBI/Veh vs. TBI/JZL195 (17.9??2.0 pA, 0.05), and TBI/Veh vs. TBI/URB597 (17.8??1.6 pA, = 0.05). A one-way ANOVA revealed no main effect of injury/treatment on sEPSC frequencies (= 0.243; Fig. 2and and = 0.002) and no main effect of injury/treatment on frequency (= 0.243). * 0.05; ** 0.01. Intrinsic Properties Following TBI and Administration of EC Degradation Inhibitors Physique SIS3 3shows a representative change in holding current used to calculate input resistance. A one-way ANOVA revealed a near-significant effect of injury/treatment on input resistance (= 0.055; Fig. 3 0.05) and TBI/Veh vs. TBI/JZL195 (62.9??4.4 M, 0.05). Physique 3shows the characteristic rebound voltage excursion seen in some neurons following hyperpolarization caused by negative current actions, known as voltage sag. A one-way ANOVA revealed no effect of injury/treatment on sag (= 0.3333; Fig. 3= 0.5233; Fig. 3= 0.055). and = 0.333) or RMP (= 0.523). * 0.05. Action Potential Generation Properties Following TBI and Administration of EC Degradation Inhibitors Physique 4shows representative traces used to calculate spike threshold. A one-way ANOVA revealed a main effect of injury/treatment on SIS3 spike threshold (= 0.002; Fig. 4 0.01) and TBI/URB597 vs. TBI/MJN110 (?39.6??1.1 mV, 0.05). Physique 4shows membrane Rabbit Polyclonal to PMS2 voltage responses to current-step inputs. Physique 4shows the FI curve constructed from the number of action potentials during each current step. SIS3 The slope of this curve between 200 and 400 pA was used to calculate FI gain. A one-way ANOVA revealed a main effect of injury/treatment on FI gain (= 0.022; Fig. 4 0.01), and TBI/URB597 (0.033??0.006 Hz/pA) vs TBI/MJN110 (0.048? 0.05 Hz/pA, 0.05). A suprathreshold current level, 400 pA, elicited firing in most (97/115) sampled neurons in the entire data set. A one-way ANOVA revealed a near-significant effect of injury/treatment on firing rate (= 0.0503; Fig. 4= 0.002). traces) to current step inputs (trace) in current-clamp recording mode used to estimate firing rate-input (FI) curves. and = 0.022) and a near-significant effect of injury/treatment on firing rate at 400 pA (= 0.0503). * 0.05, ** 0.01. Burst Firing Properties Following TBI and Administration of EC Degradation Inhibitors Physique 5shows representative burst firing patterns that were used for quantifying burst size. A one-way ANOVA revealed a main effect of injury/treatment on burst size (= 0.0005; Fig. 5 0.01), TBI/Veh (1.8??0.6) vs. TBI/MJN110 ( 0.01), and TBI/URB597 (1.3??0.2) vs. TBI/MJN110 ( 0.05). Open in a separate window Fig. 5. = 0.0005). * 0.05, ** 0.01. Coordinated Changes in Multiple Properties Following TBI and Administration of EC Degradation Inhibitors First, a smaller electrophysiological parameter set was used to more easily visualize potential separability.