Age-Dependent Changes in Synaptic NMDA Receptor Composition in Adult Human Cortical Neurons.

The molecular processes underlying the aging-related decline in cognitive performance and memory observed in humans are poorly understood. Studies in rodents have shown a decrease in N-methyl-D-aspartate receptors (NMDARs) that contain the GluN2B subunit in aging synapses, and this decrease is correlated with impaired memory functions. However, the age-dependent contribution of GluN2B-containing receptors to synaptic transmission in human cortical synapses has not been previously studied. We investigated the synaptic contribution of GluN2A and GluN2B-containing NMDARs in adult human neurons using fresh nonpathological temporal cortical tissue resected during neurosurgical procedures. The tissue we obtained fulfilled quality criteria by the absence of inflammation markers and proteomic degradation. We show an age-dependent decline in the NMDA/AMPA receptor ratio in adult human temporal cortical synapses. We demonstrate that GluN2B-containing NMDA receptors contribute to synaptic responses in the adult human brain with a reduced contribution in older individuals. With previous evidence demonstrating the critical role of synaptic GluN2B in regulating synaptic strength and memory storage in mice, this progressive reduction of GluN2B in the human brain during aging may underlie a molecular mechanism in the age-related decline in cognitive abilities and memory observed in humans.

Prospective, multicentre study of external ventricular drainage-related infections in the UK and Ireland.

OBJECTIVES: External ventricular drain (EVD) insertion is a common neurosurgical procedure. EVD-related infection (ERI) is a major complication that can lead to morbidity and mortality. In this study, we aimed to establish a national ERI rate in the UK and Ireland and determine key factors influencing the infection risk. METHODS: A prospective multicentre cohort study of EVD insertions in 21 neurosurgical units was performed over 6 months. The primary outcome measure was 30-day ERI. A Cox regression model was used for multivariate analysis to calculate HR. RESULTS: A total of 495 EVD catheters were inserted into 452 patients with EVDs remaining in situ for 4700 days (median 8 days; IQR 4-13). Of the catheters inserted, 188 (38%) were antibiotic-impregnated, 161 (32.5%) were plain and 146 (29.5%) were silver-bearing. A total of 46 ERIs occurred giving an infection risk of 9.3%. Cox regression analysis demonstrated that factors independently associated with increased infection risk included duration of EVD placement for ≥8 days (HR=2.47 (1.12-5.45); p=0.03), regular sampling (daily sampling (HR=4.73 (1.28-17.42), p=0.02) and alternate day sampling (HR=5.28 (2.25-12.38); p<0.01). There was no association between catheter type or tunnelling distance and ERI. CONCLUSIONS: In the UK and Ireland, the ERI rate was 9.3% during the study period. The study demonstrated that EVDs left in situ for ≥8 days and those sampled more frequently were associated with a higher risk of infection. Importantly, the study showed no significant difference in ERI risk between different catheter types.

The British Neurosurgical Trainee Research Collaborative: Five years on.

Since its inception in 2012, the British Neurosurgical Trainee Research Collaborative (BNTRC) has established itself as a robust example of a trainee-led research collaborative. This article summarises the work of the collaborative over its first 5 years of existence, outlining the structure, its research projects, impact and future directions.

Evidence to support mitochondrial neuroprotection, in severe traumatic brain injury.

Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms - diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.

Proposal for a prospective multi-centre audit of chronic subdural haematoma management in the United Kingdom and Ireland.

BACKGROUND. Chronic subdural haematoma (CSDH) is a common condition that increases in incidence with rising age. Evacuation of a CSDH is one of the commonest neurosurgical procedures; however the optimal peri-operative management, surgical technique, post-operative care and the role of adjuvant therapies remain controversial. AIM. We propose a prospective multi-centre audit in order to establish current practices, outcomes and national benchmarks for future studies. METHODS. Neurosurgical units (NSU) in the United Kingdom and Ireland will be invited to enrol patients to this audit. All adult patients aged 16 years and over with a primary or recurrent CSDH will be eligible for inclusion. OUTCOME MEASURES AND ANALYSIS. The proposed outcome measures are (1) clinical recurrence requiring re-operation within 60 days; (2) modified Rankin scale (mRS) score at discharge from NSU; (3) morbidity and mortality in the NSU; (4) destination at discharge from NSU and (5) length of stay in the NSU. Audit standards have been derived from published systematic reviews and a recent randomised trial. The proposed standards are clinical recurrence rate < 20%; unfavourable mRS (4-6) at discharge from NSU < 30%; mortality rate in NSU < 5%; morbidity rate in NSU < 10%. Data will be submitted directly into a secure online database and analysed by the study's management group. CONCLUSIONS. The audit will determine the contemporary management and outcomes of patients with CSDH in the United Kingdom and Ireland. It will inform national guidelines, clinical practice and future studies in order to improve the outcome of patients with CSDH.

Does low-back pain improve after decompressive spinal surgery? A prospective observational study from the British Spine Registry.

OBJECTIVE: Lumbar spine decompression surgery, in the form of laminectomy or discectomy, is known to be effective in improving symptoms of radiculopathy and neurogenic claudication. However, it is less clear how it impacts coexisting low-back pain (LBP). The aim of this study was to quantify the change in LBP after lumbar decompression. METHODS: This study analyzed data from the British Spine Registry on patients who underwent lumbar decompression surgery. LBP severity was assessed using the visual analog scale (VAS), and the primary outcome was the change in VAS score at 1 year, with secondary outcomes measuring the change in score at 6 weeks, 6 months, and 2 years. The minimal clinically important difference (MCID) was defined as a 30% reduction in pain. RESULTS: Of the 25,349 patients included in the study, 92.2% reported significant back pain at baseline. Of the entire cohort, 12,951 (55.4%) patients had follow-up data for 6 weeks, 9066 (38.8%) for 6 months, 7926 (33.9%) for 1 year, and 5517 (23.6%) for 2 years; 17,304 (68.3%) patients had follow-up data for at least one time point. Sixty-two percent of patients attained the MCID (VAS score ≥ 30%) in back pain reduction, with 51% reporting a substantial improvement (VAS score ≥ 50%). This improvement was observed by 6 weeks postoperation and was mostly maintained at 2 years. Patients with back pain predominance were more likely to attain the MCID compared with those with leg pain predominance (63.6% vs 60.1%; OR 1.16, 95% CI 1.02-1.34; p = 0.0291). Severity of baseline back pain did not reduce the proportion attaining the MCID. CONCLUSIONS: Regardless of pain presentation, LBP improves in approximately 62% of patients who undergo lumbar decompressive surgery, with 51% experiencing substantial improvement. Patients undergoing lumbar decompression can be advised on the chance of a meaningful improvement in back pain postsurgery.

Advances in Traumatic Brain Injury Biomarkers.

Traumatic brain injury (TBI) is increasingly a major cause of disability across the globe. The current methods of diagnosis are inadequate at classifying patients and prognosis. TBI is a diagnostic and therapeutic challenge. There is no Food and Drug Administration (FDA)-approved treatment for TBI yet. It took about 16 years of preclinical research to develop accurate and objective diagnostic measures for TBI. Two brain-specific protein biomarkers, namely, ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein, have been extensively characterized. Recently, the two biomarkers were approved by the FDA as the first blood-based biomarker, Brain Trauma Indicator™ (BTI™), via the Breakthrough Devices Program. This scoping review presents (i) TBI diagnosis challenges, (ii) the process behind the FDA approval of biomarkers, and (iii) known unknowns in TBI biomarker biology. The current lag in TBI incidence and hospitalization can be reduced if digital biomarkers such as hard fall detection are standardized and used as a mechanism to alert paramedics to an unresponsive trauma patient.

Comparison of Suspected and Confirmed Internal External Ventricular Drain-Related Infections: A Prospective Multicenter United Kingdom Observational Study.

Background: Diagnosis of internal external ventricular drain (EVD)-related infections (iERI) is an area of diagnostic difficulty. Empiric treatment is often initiated on clinical suspicion. There is limited guidance around antimicrobial management of confirmed versus suspected iERI. Methods: Data on patients requiring EVD insertion were collected from 21 neurosurgical units in the United Kingdom from 2014 to 2015. Confirmed iERI was defined as clinical suspicion of infection with positive cerebrospinal fluid (CSF) culture and/or Gram stain. Cerebrospinal fluid, blood, and clinical parameters and antimicrobial management were compared between the 2 groups. Mortality and Modified Rankin Scores were compared at 30 days post-EVD insertion. Results: Internal EVD-related infection was suspected after 46 of 495 EVD insertions (9.3%), more common after an emergency insertion. Twenty-six of 46 were confirmed iERIs, mostly due to Staphylococci (16 of 26). When confirmed and suspected infections were compared, there were no differences in CSF white cell counts or glucose concentrations, nor peripheral blood white cell counts or C-reactive protein concentrations. The incidence of fever, meningism, and seizures was also similar, although altered consciousness was more common in people with confirmed iERI. Broad-spectrum antimicrobial usage was prevalent in both groups with no difference in median duration of therapy (10 days [interquartile range {IQR}, 7-24.5] for confirmed cases and 9.5 days [IQR, 5.75-14] for suspected, P = 0.3). Despite comparable baseline characteristics, suspected iERI was associated with lower mortality and better neurological outcomes. Conclusions: Suspected iERI could represent sterile inflammation or lower bacterial load leading to false-negative cultures. There is a need for improved microbiology diagnostics and biomarkers of bacterial infection to permit accurate discrimination and improve antimicrobial stewardship.

Stem cells in the adult human brain.

The rapidly advancing field of stem cell research holds great promise for regenerative medicine. Regenerating brain tissue, while technically the most challenging application of stem cell biology, is also likely to reap the most reward for patients. Here, we review the current state of stem cell research in the field of human neuroscience and highlight aspects that will be of relevance to neurosurgeons.

Utility of image-guided external ventriculostomy: analysis of contemporary practice in the United Kingdom and Ireland.

OBJECTIVE: Freehand external ventricular drain (EVD) insertion is associated with a high rate of catheter misplacement. Image-guided EVD placement with neuronavigation or ultrasound has been proposed as a safer, more accurate alternative with potential to facilitate proper placement and reduce catheter malfunction risk. This study aimed to determine the impact of image-guided EVD placement on catheter tip position and drain functionality. METHODS: This study is a secondary analysis of a data set from a prospective, multicenter study. Data were collated for EVD placements undertaken in the United Kingdom and Ireland from November 2014 to April 2015. In total, 21 large tertiary care academic medical centers were included. RESULTS: Over the study period, 632 EVDs were inserted and 65.9% had tips lying free-floating in the CSF. Only 19.6% of insertions took place under image guidance. The use of image guidance did not significantly improve the position of the catheter tip on postoperative imaging, even when stratified by ventricular size. There was also no association between navigation use and drain blockage. CONCLUSIONS: Image-guided EVD placement was not associated with an increased likelihood of achieving optimal catheter position or with a lower rate of catheter blockage. Educational efforts should aim to enhance surgeons' ability to apply the technique correctly in cases of disturbed cerebral anatomy or small ventricles to reduce procedural risks and facilitate effective catheter positioning.

Sonic Hedgehog Signaling Promotes Peri-Lesion Cell Proliferation and Functional Improvement after Cortical Contusion Injury.

Traumatic brain injury (TBI) is a leading cause of death and disability globally. No drug treatments are available, so interest has turned to endogenous neural stem cells (NSCs) as alternative strategies for treatment. We hypothesized that regulation of cell proliferation through modulation of the sonic hedgehog pathway, a key NSC regulatory pathway, could lead to functional improvement. We assessed sonic hedgehog (Shh) protein levels in the cerebrospinal fluid (CSF) of patients with TBI. Using the cortical contusion injury (CCI) model in rodents, we used pharmacological modulators of Shh signaling to assess cell proliferation within the injured cortex using the marker 5-Ethynyl-2'-deoxyuridine (EdU); 50mg/mL. The phenotype of proliferating cells was determined and quantified. Motor function was assessed using the rotarod test. In patients with TBI there is a reduction of Shh protein in CSF compared with control patients. In rodents, following a severe CCI, quiescent cells become activated. Pharmacologically modulating the Shh signaling pathway leads to changes in the number of newly proliferating injury-induced cells. Upregulation of Shh signaling with Smoothened agonist (SAG) results in an increase of newly proliferating cells expressing glial fibrillary acidic protein (GFAP), whereas the Shh signaling inhibitor cyclopamine leads to a reduction. Some cells expressed doublecortin (DCX) but did not mature into neurons. The SAG-induced increase in proliferation is associated with improved recovery of motor function. Localized restoration of Shh in the injured rodent brain, via increased Shh signaling, has the potential to sustain endogenous cell proliferation and the mitigation of TBI-induced motor deficits albeit without the neuronal differentiation.

Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse.

The inactivation of glycogen synthase kinase-3beta (GSK-3beta) is proposed as the event integrating protective pathways initiated by preconditioning and other interventions. The inactivation of GSK-3 is thought to decrease the probability of opening of the mitochondrial permeability transition pore. The aim of this study was to verify the role of GSK-3 using a targeted mouse line lacking the critical N-terminal serine within GSK-3beta (Ser9) and the highly homologous GSK-3alpha (Ser21), which when phosphorylated results in kinase inactivation. Postconditioning with 10 cycles of 5 seconds of reperfusion/5 seconds of ischemia and preconditioning with 6 cycles of 4 minutes of ischemia/6 minutes of reperfusion, similarly reduced infarction of the isolated perfused mouse heart in response to 30 minutes of global ischemia and 120 minutes of reperfusion. Preconditioning caused noticeable inactivating phosphorylation of GSK-3. However, both preconditioning and postconditioning still protected hearts of homozygous GSK-3 double knockin mice. Moreover, direct pharmacological inhibition of GSK-3 catalytic activity with structurally diverse inhibitors before or after ischemia failed to recapitulate conditioning protection. Nonetheless, cyclosporin A, a direct mitochondrial permeability transition pore inhibitor, reduced infarction in hearts from both wild-type and homozygous GSK-3 double knockin mice. Furthermore, in adult cardiac myocytes from GSK-3 double knockin mice, insulin exposure was still as effective as cyclosporin A in delaying mitochondrial permeability transition pore opening. Our results, which include a novel genetic approach, suggest that the inhibition of GSK-3 is unlikely to be the key determinant of cardioprotective signaling in either preconditioning or postconditioning in the mouse.

Enduring Neuroprotective Effect of Subacute Neural Stem Cell Transplantation After Penetrating TBI.

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including "The Lancet Neurology Commission" and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection.

Assessment of precision and reproducibility of a new myograph.

BACKGROUND: The physiological characteristics of muscle activity and the assessment of muscle strength represent important diagnostic information. There are many devices that measure muscle force in humans, but some require voluntary contractions, which are difficult to assess in weak or unconscious patients who are unable to complete a full range of voluntary force assessment tasks. Other devices, which obtain standard muscle contractions by electric stimulations, do not have the technology required to induce and measure reproducible valid contractions at the optimum muscle length. METHODS: In our study we used a newly developed diagnostic device which measures accurately the reproducibility and time-changed-variability of the muscle force in an individual muscle. A total of 500 in-vivo measurements of supra-maximal isometric single twitch contractions were carried out on the musculus adductor pollicis of 5 test subjects over 10 sessions, with ten repetitions per session. The same protocol was performed on 405 test subjects with two repetitions each to determine a reference-interval on healthy subjects. RESULTS: Using our test setting, we found a high reproducibility of the muscle contractions of each test subject. The precision of the measurements performed with our device was 98.74%. Only two consecutive measurements are needed in order to assess a real, representative individual value of muscle force. The mean value of the force of contraction was 9.51 N and the 95% reference interval was 4.77-14.25 N. CONCLUSION: The new myograph is a highly reliable measuring device with which the adductor pollicis can be investigated at the optimum length. It has the potential to become a reliable and valid tool for diagnostic in the clinical setting and for monitoring neuromuscular diseases.

Amelioration of Penetrating Ballistic-Like Brain Injury Induced Cognitive Deficits after Neuronal Differentiation of Transplanted Human Neural Stem Cells.

Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies with penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread perilesional neurodegeneration, similar to that seen in humans following gunshot wound to the head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Toward this objective, green fluorescent protein (GFP) labeled hNSC (400,000 per animal) were transplanted in immunosuppressed Sprague-Dawley (SD), Fisher, and athymic (ATN) PBBI rats 1 week after injury. Tacrolimus (3 mg/kg 2 days prior to transplantation, then 1 mg/kg/day), methylprednisolone (10 mg/kg on the day of transplant, 1 mg/kg/week thereafter), and mycophenolate mofetil (30 mg/kg/day) for 7 days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8 weeks post-transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16 weeks post-transplantation, neither cell proliferation nor glial lineage markers were detected. Transplanted cell morphology was similar to that of neighboring host neurons, and there was relatively little migration of cells from the peritransplant site. By 16 weeks, GFP-positive processes extended both rostrocaudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing the internal capsule, and extending ∼13 mm caudally from transplantation site reaching into the brainstem. In a Morris water maze test at 8 weeks post-transplantation, animals with transplants had shorter latency to platform than vehicle-treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits of durable engraftment and neuronal differentiation. Therefore, these results justify further studies to progress towards clinical translation of hNSC therapy for PTBI.

Hypothermia in Traumatic Brain Injury.

For over 50 years, clinicians have used hypothermia to manage traumatic brain injury (TBI). In the last two decades numerous trials have assessed whether hypothermia is of benefit in patients. Mild to moderate hypothermia reduces the intracranial pressure (ICP). Randomized control trials for short-term hypothermia indicate no benefit in outcome after severe TBI, whereas longer-term hypothermia could be of benefit by reducing ICP. This article summarises current evidence and gives recommendations based upon the conclusions.

Endoscopic biopsy and third ventriculostomy for the management of pineal region tumors.

OBJECTIVE: To assess the histologic accuracy of endoscopic biopsy samples of the pineal region. Pineal region tumors usually present with acute hydrocephalus. Histologic diagnosis is paramount, as it greatly influences treatment. Endoscopic techniques can combine histologic diagnosis with relief of the obstructive hydrocephalus in a single operation. Because pineal region tumors can be heterogeneous, initial biopsy samples may not represent the most aggressive portion of the tumor. METHODS: This retrospective study reviews our experience of endoscopic third ventriculostomy combined with biopsy of the lesion. The histologic diagnosis as a result of the initial biopsy was compared with the final histologic diagnosis to establish the accuracy of the endoscopic biopsy sample in aiding diagnosis. RESULTS: Forty-seven patients underwent an endoscopic third ventriculostomy. All but 1 patient underwent a concurrent biopsy of the space-occupying lesion and 39 of 46 patients (85%) had a histologic diagnoses. In the remaining 7 patients (15%), the histology was negative; in 6 cases, the second attempt to obtain a histologic diagnosis was successful (2 repeat endoscopic biopsy samples, 2 resections, 2 stereotactic biopsy samples). In 1 patient a presumed low-grade tectal tumor was followed up with sequential scanning. Twenty-eight patients underwent subsequent operations (24 resections, 4 stereotactic biopsies). In 6 of 28 patients (21%), the histologic report was amended after the second procedure. CONCLUSIONS: The endoscopic biopsy sample yields an accurate histologic diagnosis for most pineal region tumors, with a positive histologic sample in about 85% of patients. However, the results must be interpreted cautiously, as the heterogeneous nature of these tumors may lead to an approximately 21% error rate in the initial tumor diagnosis.

Endogenous GFAP-positive neural stem/progenitor cells in the postnatal mouse cortex are activated following traumatic brain injury.

Interest in promoting regeneration of the injured nervous system has recently turned toward the use of endogenous stem cells. Elucidating cues involved in driving these precursor cells out of quiescence following injury, and the signals that drive them toward neuronal and glial lineages, will help to harness these cells for repair. Using a biomechanically validated in vitro organotypic stretch injury model, cortico-hippocampal slices from postnatal mice were cultured and a stretch injury equivalent to a severe traumatic brain injury (TBI) applied. In uninjured cortex, proliferative potential under in vitro conditions is virtually absent in older slices (equivalent postnatal day 15 compared to 8). However, following a severe stretch injury, this potential is restored in injured outer cortex. Using slices from mice expressing a fluorescent reporter on the human glial fibrillary acidic protein (GFAP) promoter, we show that GFAP+ cells account for the majority of proliferating neurospheres formed, and that these cells are likely to arise from the cortical parenchyma and not from the subventricular zone. Moreover, we provide evidence for a correlation between upregulation of sonic hedgehog signaling, a pathway known to regulate stem cell proliferation, and this restoration of regenerative potential following TBI. Our results indicate that a source of quiescent endogenous stem cells residing in the cortex and subcortical tissue proliferate in vitro following TBI. Moreover, these proliferating cells are multipotent and are derived mostly from GFAP-expressing cells. This raises the possibility of using this endogenous source of stem cells for repair following TBI.

Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase.

The expression and function of the 8 distinct catalytic isoforms of PI 3-kinase (PI3K) in the nervous system are unknown. Whereas most PI3Ks have a broad tissue distribution, the tyrosine kinase-linked p110delta isoform has previously been shown to be enriched in leukocytes. Here we report that p110delta is also highly expressed in the nervous system. Inactivation of p110delta in mice did not affect gross neuronal development but led to an increased vulnerability of dorsal root ganglia neurons to exhibit growth cone collapse and decreases in axonal extension. Loss of p110delta activity also dampened axonal regeneration following peripheral nerve injury in adult mice and impaired functional recovery of locomotion. p110delta inactivation resulted in reduced neuronal signaling through the Akt protein kinase, and increased activity of the small GTPase RhoA. Pharmacological inhibition of ROCK, a downstream effector of RhoA, restored axonal extension defects in neurons with inactive p110delta, suggesting a key role of RhoA in p110delta signaling in neurons. Our data identify p110delta as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system.