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Chronic Cognitive Dysfunction After Traumatic Brain Injury Is Improved With A Phosphodiesterase 4B Inhibitor Titus DJ, Wilson NM, Freund JE, Carballosa MM, Sikah KE, Furones C, Dietrich WD, Gurney ME, Atkins CM. 2016. Journal of Neuroscience 36(27):7095-7108 Patricia Olson, MS3, PhD SIGN Journal Club October 11, 2016 Disclosures There are no potential conflicts of interest to disclose. Background • TBI • Learning and Memory – Hippocampus – LTP and synaptic plasticity • cAMP, CREB, PDE4B Traumatic Brain Injury • Leading cause of death in North America for individuals ages 145yo – motor vehicle accidents, violence, combat-related trauma • Incidence: 538.2 per 100,000 • Prevalence of long-term disability related to TBI in the US: 3.25.3 million; approx 1-2% of population Clinical Diagnosis • Glasgow Coma Scale (GCS) is universally accepted tool for TBI classification – 15-point scale: Eye, Motor, Verbal – Limited by confounding factors: • sedation, paralysis, intoxication, endotracheal intubation • Full Outline of UnResponsiveness (FOUR) Score – 17-point scale: Eye, Motor, Brainstem, Breathing • CT-based grading scales: Marshall scale and Rotterdam scale Predicts the risk of increased ICP and outcome in adults accurately, but lacks reproducibility in patients with multiple types of brain injury. Pathophysiology: Primary Brain Injury • Occurs at the time of trauma – Direct impact – rapid acceleration/deceleration penetrating injury blast waves • External mechanical forces transfer to intracranial contents – Shearing mechanisms lead to diffuse axonal injury (DAI) – Focal cerebral contusions – Extra-axial hematomas Pathophysiology: Secondary Brain Injury • Cascade of molecular injury mechanisms • Initiated at the time of initial trauma, can continue for hours or days – – – – – – – Neurotramitter-mediated excitotoxicity of glutamate causing free-radical injury Cellular injury causing second-messenger dysfunction Electrolyte imbalances Mitochondrial dysfunction Inflammatory responses Apoptosis Secondary ischemia from vasospasm, focal microvasuclar occulsion, vascular injury Cellular injury causing second-messenger dysfunction: • TBI results in CREB activation deficits during learning • Decreased cAMP signaling and reduced cAMP-responseelement-binding protein (CREB) activation. Current Treatment: • Phosphodiesterase 4 Inhibitors – Rolipram (pan-PDE4 inhibitor) – Roflumilast • Side effects include – GI: Diarrhea, Nausea, Emesis, Abdominal Pain, Decreased Appetite, Weight loss – CNS: Headache, Insomnia, Depression – Worsens pathology despite improving cognition Problem: Over 3 million individuals are living w/chronic TBI disabilities and 7085% report learning and memory impairments. Hypothesis: A selective PDE4B inhibitor (A33) can decrease learning and memory impairments and thus decreasing the expression of hippocampal LTP, thus reversing the learning deficits induced by TBI. Memory: Implicit and Explicit Implicit Memory • Associative and Non-Associative – Fear Conditioning involves the Amygdala – Operant conditioning involves the striatum and cerebellum – Classical Conditioning, sensitization, and habituation involve the sensory and motor systems – Simple reflexes involve the spinal cord Explicit Memory: – Four processes: Encoding, Consolidation, Storage, Retrieval The Hippocampus and LTP: the Storage of Declarative Memory A high-frequency train of stimuli applied to fibers afferent to the hippocampus increase the amplitude of EPSPs in the target neurons. The increase lasts for days or weeks and requires activation of several afferent axons together. This property has been termed cooperativity, and it results from the requirement of NMDA receptors that glutamate bind them and that the cell be hypopolarized, the binding opens the channel and the hypopolarization displaces Mg++ that blocks the channel lumen. Also required is that the pre-and post-synaptic cells both be active at the same time. This property is termed associativity. LTP, Learning and Memory, and CREB • Long-term memory is represented at the cellular level by activity-dependent modulation of both the function and the structure of specific synaptic connections • these synapses depend on the activation of specific patterns of gene expression • Inhibition of transcription or translation can block the formation of long-term memory Early Phase vs. Late Phase NMDAR = coincidence detectors Problem: Over 3 million individuals are living w/chronic TBI disabilities and 7085% report learning and memory impairments. Hypothesis: A selective PDE4B inhibitor (A33) can decrease learning and memory impairments and thus decreasing the expression of hippocampal LTP, thus reversing the learning deficits induced by TBI. Methods • • • • • Fluid-Percussion Injury Surgery Drug administration Electrophysiological recordings Eliza, Western Fear Conditioning, Water Maze Fluid-Percussion Injury • Reproducible, Scalable (mild, moderate, severe injury) • Brain injury is induced by a rapid (~20ms) fluid pulse through a craniotomy onto the intact dura that follows the inner curvature of the skull and creates an elastic decompression of the brain • The mechanical forces disrupt cell membranes, blood vessels, and neuronal processes. Electrophysiology • 12 weeks post-surgery • ipsilateral hippocampus dissected into 440μM transverse slices • Field EPSPs were recorded from CA1 striatum radiatum – Hippocampal slices were treated w/vehicle or 300nM A33 – Stepwise current increases from 20 to 240μA • Paired-pulse facilitation was measured • LTP was induced by high-frequency stimulation using a single train of 100 pulses delivered at 100Hz Schaffer Collateral Pathway The experimental setup for demonstrating LTP is shown here: Recordings are made intracellularly from CA1 neurons of the hippocampus while stimulation is applied to Schaffer Collaterals of CA3 neurons. The amplitudes of the EPSPs in the CA1 neurons are shown in B. For a single stimulus, the amplitude of the EPSPs is plotted at 100%. When a train of stimuli is applied instead, the amplitude of the EPSPs augment to about 150%, whereas with 4 such trains, the amplitude increases to 250%. Many people think that long-term potentiation is an example of Hebb’s rule at work and that it is the physiological basis of memory. Hypothesis A selective PDE4B inhibitor (A33) can decrease learning and memory impairments and thus decreasing the expression of hippocampal LTP, thereby reversing the learning deficits induced by TBI. Fig 1A: A33 bath application to TBI slices reversed the depression in basal synaptic transmission. Fig 1B: A33 did not rescue the decrease in PPF caused by TBI Fig 1C: A33 improved LTP expression impaired by TBI Fig 1D and 1E: A33 significantly rescued the maintenance phase of LTP and these changes were not due to differences in depolarization during the tetanus Early Phase vs. Late Phase NMDAR = coincidence detectors A33 and TNF-α • PDE4B regulates expression of proinflammatory cytokine TNF-α in circulating leukocytes and resident MΦ • To determine whether TNF-α was elevated in the injured brain at 6 hours post-injury, the ipsilateral parietal cortex and hippocampus were assayed by ELISA for TNF-α levels • 0.33mg/kg A33 administered 30 min post-injury and 1 h before animal was sacked. PDE4B regulates expression of proinflammatory cytokine TNF-α in circulating leukocytes and resident MΦ Fig 2B: A33 treatment significantly reduced TNF-α levels in TBI animals Fig 2C and 2D: Although PDE4 isoforms were present in the hippocampus 3 months post-surgery, there was not a difference in protein levels between sham and TBI animals Does PDE4B inhibition by A33 improve chronic learning and memory deficits after TBI • Post-surgery recovery: 3 months w/o treatment • Animals received A33 (0.3mg/kg i.p.) or vehicle 30 minutes before training • Then tested serially on: – fear conditioning 12 and 16 weeks post-surgery – water maze 13 weeks post-surgery – working memory 14 weeks post-surgery A33 or vehicle were administered 30 minutes before behavioral training on the indicated days (arrows). Fig 3B—Contextual Test At both 24h and 1 month after training, TBI animals treated w/vehicle demonstrated significantly less contextual fear conditioning compared w/sham animals treated w/vehicle or TBI animals treated w/ A33 Fig 3C—Cued Test There was no significant interaction of surgery x drug treatment for either time point in baseline freezing; however, when freezing in response to the cue was assessed, there was significant interaction of surgery x drug treatment at both time points. Fig 3D: These fear conditioning differences were not due to changes in shock sensitivity since the minimal shock threshold to elicit a flinch, jump, or vocalization was not significantly different between animal groups. To determine whether A33 would improve learning in another hippocampal-dependent learning task, the same cohort of animals were tested in a water maze at 13 weeks post-surgery using a hidden platform. Escape latency and path length to find the hidden platform were significantly impaired in TBI animals compared to sham animals. There was a main effect of A33 drug treatment for path length during acquisition. A33 treatment significantly improves long-term spatial memory retention. Fig 3F and 3G: TBI animals treated with vehicle spent significantly less time in the target quadrant compared with sham animals treated with vehicle or A33, or TBI animals treated with A33. The number of platform zone crossings were also significantly less in TBI animals treated with vehicle versus A33, or sham animals treated with vehicle or A33. Fig 5: Working memory A modified water maze to assess spatial working memory at 14 weeks post-surgery: The animals were trained to locate a hidden platform that remains invariant only between pairs of trials by 5sec. TBI animals had significantly longer escape latencies compared with sham animals and A33 treatment improved working memory in both sham and TBI animals. Fig 6: Cortical and hippocampal volume was measured at the completion of behavioral testing: Significant cortical atrophy was observed in TBI animals. There was no effect of A33 treatment. These results indicate that intermittent A33 treatment did not improve pathology in the chronic TBI recovery period. Conclusions • A33 (a selective PDE4B inhibitor) has procognitive benefits when administered 3 months postinjury • A33 was also shown to – Improve hippocampal LTP – Cross the BBB at relevant concentrations – Improve performance in learning tasks • Tx w/a PDE4B inhibitor may address hypofunction in the signaling pathways that use CREB phosphorylation, namely those involved in memory formation in the hippocampus Take-Away Short-term treatment w/a PDE4B inhibitor improves synaptic plasticity, learning and memory when delivered at the time of learning at 3 months after TBI, and thus can alter chronic reduction of neurogenesis Strengths • Comprehensive study – Molecular to behavioral • Translatable Weaknesses Neither the study nor the discussion addressed • The role of the amygdala in fear conditioning • The role of synaptic function in the context of an ensemble of neurons in a neural circuit in the formation of complex memories • The role of modulatory transmitters (DA, Ach) in the retrieval process. References • Hemphill JC, Phan N. 2016. Traumatic brain injury: Epidemiology, classification, and pathophysiology. Up to Date. • Kandel ER. 2012. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Molecular Brain 5:14. • Lifshitz, J. 2009. Animal Models of Acute Neurological Injuries pp369384 • Mann, M. 2011. Learning and Memory.