Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.

In vitro neuronal network activity in NMDA receptor encephalitis.

BACKGROUND: Anti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR) and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma. RESULTS: We describe effects of cerebrospinal fluid (CSF) from an anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patient on in vitro neuronal network activity (ivNNA). In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA) system.The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF) taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease. CONCLUSION: Patient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

Episodic itch in a case of spinal glioma.

BACKGROUND: Itch is a frequent complaint reported by patients and is usually ascribed to dermatological or metabolic causes. In neurological disorders, however, it is a very unusual symptom and thus its neurological aetiology is likely to be overlooked. There are only very few reports about permanent itch related to lesions of the central nervous system. To our knowledge we report the first case of episodic itch associated with a central nervous lesion. CASE PRESENTATION: A 74-year-old female suffered from long-standing episodes of itch of the dermatomes C2 to C6 on the right side that was refractory to any treatment. On occurrence it propagated in a proximal to distal fashion. Between the episodes the patient was asymptomatic. MRI of the cervical spine uncovered a spinal glioma that matched the location of the symptoms. Treatment with gabapentin led to a prompt reduction of the symptoms. CONCLUSION: Patients with intractable pruritus and dermatomal presentation ought to undergo neurological examination and spinal cord imaging. Thus, ongoing frustrating and sometimes even harmful treatment trials could be avoided.

Encephalopathic Susac's Syndrome associated with livedo racemosa in a young woman before the completion of family planning.

BACKGROUND: Susac's Syndrome (SS) consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss (HL). Histopathologically, SS is characterised by a microangiopathy, and some observations suggest that an immune-mediated damage of endothelial cells might play a role. These findings also implicate a similarity between SS and other autoimmune diseases, most notably juvenile dermatomyositis (JDM). However, SS and JDM are commonly thought to affect distinct and non-overlapping sets of organs, and it is currently not clear how these specificities arise. Moreover, in the absence of clinical trials, some authors suggest that therapeutic approaches in SS should rely on the model of other autoimmune diseases such as JDM. CASE PRESENTATION: Here, we report a case of SS in a 32-year-old pregnant woman. She initially was admitted to the hospital with subacute severe encephalopathy and multifocal neurologic signs. As cranial magnetic resonance imaging (MRI) revealed multifocal white matter lesions including the corpus callosum, erroneously a diagnosis of multiple sclerosis (MS) was made, and intravenous methylprednisolone (IVMP) therapy was initiated. A few days later, an exanthema appeared on the trunk and extremities, which was diagnosed as livedo racemosa (LR). Several weeks later, the patient was readmitted to the clinic with an obscuration of her left visual hemifield and a bilateral HL. Ophthalmologic examination revealed extensive ischemic damage to both retinae. Now the correct diagnosis of SS was established, based on the above triad of clinical symptoms in conjunction with typical MRI and fundoscopic findings. When SS was diagnosed, the standard therapy with intravenous cyclophosphamide (IVCTX) was not instituted because of a significant risk of permanent infertility. Instead, sustained control of disease activity could be achieved with a therapeutic regime combining prednisolone, intravenous immunoglobulins (IVIG), mycophenylate mofetil (MM), and methotrexate (MTX). CONCLUSIONS: An association with LR has only been described in very few cases of SS before and further underlines the pathogenetic relationship between SS and other autoimmune diseases such as JDM. In young women with SS and the desire for a child the combination of MM and MTX may represent a reasonable alternative to IVCTX.

Restoring neuronal function after stroke by cell replacement: anatomic and functional considerations.

BACKGROUND AND PURPOSE: A major challenge to effective treatment after stroke is the restoration of neuronal function. In recent years, cell-based therapies for stroke have been explored in experimental animal models, and the results have suggested behavioral improvements. However, the anatomic targets of a cell-based stroke therapy and the relationship of cell grafts to post stroke reorganization are poorly understood, which results in difficulties defining strategies for neuronal substitution. Given that stroke causes a variety of secondary changes at locations beyond the infarct lesion, overcoming these difficulties is even more important. SUMMARY OF REVIEW: We describe which brain structures and cell types are candidates for substitution and how new neuronal functionality could be implemented in a damaged brain by capitalizing on current concepts of post stroke plasticity.

Cerebrospinal fluid of brain trauma patients inhibits in vitro neuronal network function via NMDA receptors.

Neurological diseases frequently induce pathological changes of cerebrospinal fluid (CSF) that might secondarily influence brain activity, as the CSF-brain barrier is partially permeable. However, functional effects of CSF on neuronal network activity have not been specified to date. Here, we report that CSF specimens from patients with reduced Glasgow Coma Scale values caused by severe traumatic brain injury suppress synchronous activity of in vitro-generated neuronal networks in comparison with controls. We present evidence that underlying mechanisms include increased N-methyl-D-aspartate receptor activity mediated by a CSF fraction containing elevated amino acid concentrations. These proof-of-principle data suggest that determining effects of CSF specimens on neuronal network activity might be of diagnostic value.

Encephalopathy associated with autoimmune thyroid disease in patients with Graves' disease: clinical manifestations, follow-up, and outcomes.

BACKGROUND: The encephalopathy associated with autoimmune thyroid disease (EAATD) is characterized by neurological/psychiatric symptoms, high levels of anti-thyroid antibodies, increased cerebrospinal fluid protein concentration, non-specific electroencephalogram abnormalities, and responsiveness to the corticosteroid treatment in patients with an autoimmune thyroid disease. Almost all EAATD patients are affected by Hashimoto's thyroiditis (HT), although fourteen EAATD patients with Graves' disease (GD) have been also reported. METHODS: We have recorded and analyzed the clinical, biological, radiological, and electrophysiological findings and the data on the therapeutic management of all GD patients with EAATD reported so far as well as the clinical outcomes in those followed-up in the long term. RESULTS: Twelve of the fourteen patients with EAATD and GD were women. The majority of GD patients with EAATD presented with mild hyperthyroidism at EAATD onset or shortly before it. Active anti-thyroid autoimmunity was detected in all cases. Most of the patients dramatically responded to corticosteroids. The long term clinical outcome was benign but EAATD can relapse, especially at the time of corticosteroid dose tapering or withdrawal. GD and HT patients with EAATD present with a similar clinical, biological, radiological, and electrophysiological picture and require an unaffected EAATD management. CONCLUSIONS: GD and HT equally represent the possible background condition for the development of EAATD, which should be considered in the differential diagnosis of all patients with encephalopathy of unknown origin and an autoimmune thyroid disease, regardless of the nature of the underlying autoimmune thyroid disease.

Neural precursor cells as a novel target for interferon-beta.

The immunomodulating agent interferon-beta (IFNbeta) is administered therapeutically in several autoimmune diseases and endogenously released by immune cells during diverse infections. As in recent years a variety of pro- and anti-inflammatory substances were shown to influence significantly neural precursor cells that are implicated in a variety of regenerative mechanisms but also in tumor growth, we studied a possible effect of IFNbeta on neural precursor cells derived from murine embryonic day 14 neurospheres. First, we demonstrated that interferon type-I receptors are expressed on neural precursor cells and that these cells respond to IFNbeta treatment by up-regulating IFNbeta inducible genes including Myxovirus 1 and viperin. Furthermore, we could show for the first time that IFNbeta treatment significantly inhibited the proliferation of neural precursor cells possibly through induction of p21, a cyclin-dependent kinase inhibitor. IFNbeta did not exert cytotoxic or neuroprotective effects and we could not see effects on the differentiation of neural precursor cells into total amounts of neurons, astrocytes or oligodendrocytes. However, we found that IFNbeta markedly diminished neurite outgrowth and neuronal maturation of neural precursor-derived neurons.

Niche-dependent development of functional neuronal networks from embryonic stem cell-derived neural populations.

BACKGROUND: The present work was performed to investigate the ability of two different embryonic stem (ES) cell-derived neural precursor populations to generate functional neuronal networks in vitro. The first ES cell-derived neural precursor population was cultivated as free-floating neural aggregates which are known to form a developmental niche comprising different types of neural cells, including neural precursor cells (NPCs), progenitor cells and even further matured cells. This niche provides by itself a variety of different growth factors and extracellular matrix proteins that influence the proliferation and differentiation of neural precursor and progenitor cells. The second population was cultivated adherently in monolayer cultures to control most stringently the extracellular environment. This population comprises highly homogeneous NPCs which are supposed to represent an attractive way to provide well-defined neuronal progeny. However, the ability of these different ES cell-derived immature neural cell populations to generate functional neuronal networks has not been assessed so far. RESULTS: While both precursor populations were shown to differentiate into sufficient quantities of mature NeuN+ neurons that also express GABA or vesicular-glutamate-transporter-2 (vGlut2), only aggregate-derived neuronal populations exhibited a synchronously oscillating network activity 24 weeks after initiating the differentiation as detected by the microelectrode array technology. Neurons derived from homogeneous NPCs within monolayer cultures did merely show uncorrelated spiking activity even when differentiated for up to 12 weeks. We demonstrated that these neurons exhibited sparsely ramified neurites and an embryonic vGlut2 distribution suggesting an inhibited terminal neuronal maturation. In comparison, neurons derived from heterogeneous populations within neural aggregates appeared as fully mature with a dense neurite network and punctuated vGlut2 expression within presynaptic vesicles. Also those NPCs that had migrated away from adherent neural aggregates maintained their ability to generate a synchronously oscillating neuronal network, even if they were separated from adherent aggregates, dissociated and re-plated. CONCLUSION: These findings suggest that the complex environment within niches and aggregates of heterogeneous neural cell populations support the generation of fully mature neurons and functional neuronal networks from ES cell-derived neural cells. In contrast, homogeneous ES cell-derived NPCs within monolayer cultures exhibited an impaired functional neuronal maturation.

Isolated unilateral temporal muscle hypertrophy: a rare cause of hemicranial headache.

A case of isolated unilateral hypertrophy of the Musculus temporalis identified by magnetic resonance imaging associated with recurrent hemicranial headache in a 22-year-old woman with Turkish ancestry is presented. Symptomatic relief was achieved by administration of acetaminophen. A review of the literature is presented and additional treatment options are discussed.

In vitro neuronal network activity as a new functional diagnostic system to detect effects of Cerebrospinal fluid from autoimmune encephalitis patients.

The intent of this study was to investigate if cerebrospinal fluid (CSF) from autoimmune encephalitis (AE) patients regulates in vitro neuronal network activity differentially to healthy human control CSF (hCSF). To this end, electrophysiological effects of CSF from AE patients or hCSF were measured by in vitro neuronal network activity (ivNNA) recorded with microelectrode arrays (MEA). CSF from patients with either N-methyl-D-aspartate-receptor-antibody (pCSFNMDAR, n = 7) or Leucine-rich-glioma-inactivated-1-Ab (pCSFLGI1, n = 6) associated AE suppressed global spiking activity of neuronal networks by a factor of 2.17 (p < 0.05) or 2.42 (p < 0.05) compared to hCSF. The former also suppressed synchronous network bursting by a factor of 1.93 (p < 0.05) in comparison to hCSF (n = 13). As a functional diagnostic test, this parameter reached a sensitivity of 86% for NMDAR-Ab- and 100% for LGI1-Ab-associated AE vs. hCSF at a specificity of 85%. To explore if modulation at the NMDAR influences effects of hCSF or pathological CSF, we applied the NMDAR-antagonist 2-Amino-5-phosphono-pentanoic acid (AP5). In CSF from NMDAR-Ab-associated AE patients, spike rate reduction by AP5 was more than 2-fold larger than in hCSF (p < 0.05), and network burst rate reduction more than 18-fold (p < 0.01). Recording ivNNA might help discriminating between functional effects of CSF from AE patients and hCSF, and thus could be used as a functional diagnostic test in AE. The pronounced suppression of ivNNA by CSF from NMDAR-Ab-associated AE patients and simultaneous antagonism at the NMDAR by AP5, particularly in burst activity, compared to hCSF plus AP5, confirms that the former contains additional ivNNA-suppressing factors.

Neural cell adhesion molecule L1-transfected embryonic stem cells promote functional recovery after excitotoxic lesion of the mouse striatum.

We have generated a murine embryonic stem cell line constitutively expressing L1 at all stages of neural differentiation to investigate the effects of L1 overexpression on stem cell proliferation, migration, differentiation, cell death, and ability to influence drug-induced rotation behavior in an animal model of Huntington's disease. L1-transfected cells showed decreased cell proliferation in vitro, enhanced neuronal differentiation in vitro and in vivo, and decreased astrocytic differentiation in vivo without influencing cell death compared with nontransfected cells. L1 overexpression also resulted in an increased yield of GABAergic neurons and enhanced migration of embryonic stem cell-derived neural precursor cells into the lesioned striatum. Mice grafted with L1-transfected cells showed recovery in rotation behavior 1 and 4 weeks, but not 8 weeks, after transplantation compared with mice that had received nontransfected cells, thus demonstrating for the first time that a recognition molecule is capable of improving functional recovery during the initial phase in a syngeneic transplantation paradigm.

Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats.

Stroke represents one of the leading causes of death and disability in Western countries, but despite intense research, only few options exist for the treatment of stroke-related infarction of brain tissue. In experimental stroke, cell therapy can partly reverse some behavioural deficits. However, the underlying mechanisms have remained unknown as most studies revealed only little, if any, evidence for neuronal replacement and the observed behavioural improvements appeared to be related rather to a graft-derived induction of a positive response in the remaining host tissue than to cell replacement by the graft itself. The present study was performed to test a murine embryonic stem cell (ESC)-based approach in rats subjected to endothelin-induced middle cerebral artery occlusion. Efficacy of cell therapy regarding graft survival, neuronal yield and diversity, and electrophysiological features of the grafted cells were tested after transplanting ESC-derived neural precursors into the infarct core and periphery of adult rats. Here, we show that grafted cells can survive, albeit not entirely, most probably as a consequence of an ongoing immune response, within the infarct core for up to 12 weeks after transplantation and that they differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse neurotransmitter-subtypes. Most importantly, transplanted cells demonstrate characteristics of electrophysiologically functional neurons with voltage-gated sodium currents that enable these cells to fire action potentials. Additionally, during the first 7 weeks after transplantation we observed spontaneous excitatory post-synaptic currents in graft-derived cells indicating synaptic input. Thus, our observations show that ESC-based regenerative approaches may be successful in an acutely necrotic cellular environment.

Dementia with Lewy bodies: cerebrospinal fluid suppresses neuronal network activity.

One of the core clinical criteria of Dementia with Lewy bodies (DLB) are fluctuations of cognition. Underlying processes may be rather functional than neurodegenerative, reflected by, for example, factors present in cerebrospinal fluid (CSF). The aim of this study was to identify in-vitro neuronal network activity (ivNNA) changes of CSF from DLB patients compared with patients with Parkinson's disease (PD) and controls. Primary neuronal mouse cultures were grown on microelectrode arrays to record ivNNA when exposed to respective CSF samples. If exposed to CSF of DLB patients, ivNNA showed a reduced spike rate and burst rate compared with CSF of PD patients and controls. Our data are suggestive of the presence of functional factors in the CSF of DLB patients that differentiate network activity from PD patients and controls. Future studies should evaluate whether this pilot observation might be related to fluctuations of cognition in DLB.

A new role for the cell adhesion molecule L1 in neural precursor cell proliferation, differentiation, and transmitter-specific subtype generation.

Adhesion molecules play important roles in the development and regeneration of the CNS and PNS. We found that the immunoglobulin superfamily recognition molecule L1 influences proliferation and differentiation of neural precursor cells. Substrate-coated L1 reduced proliferation of precursor cells in a dose-dependent manner and increased neuronal and decreased astrocytic differentiation when compared with poly-l-lysine or laminin substrates. Enhancement of neuronal differentiation was more effective if L1 was offered via the cell surface of transfected fibroblasts compared with substrate-coated purified L1. Furthermore, L1 decreased cholinergic-subtype differentiation and accelerated GABAergic differentiation of precursor cell-derived neurons in comparison with poly-l-lysine or laminin. Generation of dopaminergic neurons was not influenced by L1. Experiments with precursor cells generated from L1-deficient mice indicate that L1 acts via heterophilic interaction on proliferation and differentiation of L1-negative precursor cells and via a homophilic or L1 coreceptor-mediated interaction on maturation of precursor cell-derived L1-positive neurons. Clonal analysis revealed that L1 equally inhibits proliferation of monopotential, bipotential, and multipotential precursor cells, but selectively enhances neuronal differentiation of multipotential and bipotential neuron-astrocyte precursors. Our observations support a new role for L1 or L1 ligands in neural precursor cell proliferation and differentiation.

Cell adhesion molecule l1-transfected embryonic stem cells with enhanced survival support regrowth of corticospinal tract axons in mice after spinal cord injury.

Previous studies have indicated that the cell adhesion molecule L1 enhances neuronal survival and neurite outgrowth. L1-mediated promotion of neurite outgrowth has been shown to occur also in an inhibitory environment not only in vitro, but also in vivo. To further investigate the effects of L1 in spinal cord injury, we transfected embryonic stem cells with a plasmid encoding the full-length mouse L1 molecule under the control of PGK promoter. An embryonic stem cell line derived from C57BL/6J transgenic mice that express green fluorescent protein under control of the beta-actin promoter was transfected with L1 and injected into the lesion site of 3-month-old C57BL/6J female mice 7 days after compression injury. Non-transfected embryonic stem cells were detectable at the lesion site 3 days after transplantation, but lost their cellular integrity 7 days after transplantation and were barely detectable 1 month after transplantation. In contrast, L1-transfected embryonic stem cells were detected 1 month after transplantation in numbers comparable to those of the injected cells and demonstrated extended processes. Further, in contrast to the few detectable nontransfected stem cells that remained at the injection site 1 month post-transplantation, the L1-transfected embryonic stem cells had migrated rostrally and caudally from the lesion. Anterogradely labeled corticospinal tract axons showed interdigitation with L1-transfected embryonic stem cells and, in contrast to non-transfected stem cells, extended into the lesion site 1 month after transplantation and, in some cases, extended beyond it. Our observations encourage the use of L1-transfected embryonic stem cells that express L1 not only at the cell surface, but also as a soluble and secreted form. Their use could condition the inhibitory environment for homophilic L1-enhanced axon regrowth not only in spinal cord regeneration, but also in other lesion paradigms.

Freshly frozen E18 rat cortical cells can generate functional neural networks after standard cryopreservation and thawing procedures.

Primary dissociated brain tissue from rodents is widely used in a variety of different scientific methods to investigate cellular processes in vitro. Often, for this purpose cell cultures need to be generated just on time, requiring extensive animal lab infrastructure. We show here that cryopreservation and thawing of dissociated tissue from rat cerebral cortex at embryonic day 18 is feasible without affecting its ability to form functional neuronal networks in vitro. Vitality of fresh and re-thawed cortical cells was comparable, assessed by CellTiter-Blue-assay, CytoTox-ONE assay, immunocytochemical characterization and in vitro neuronal network activity recordings on microelectrode arrays. These findings suggest that planning and execution of experiments might be considerably facilitated by using cryo-preserved neurons instead of acutely dissociated neural cultures due to fewer logistical issues with regard to animal breeding and pregnancy timed preparations.

Different mechanisms of secondary neuronal damage in thalamic nuclei after focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: After focal cerebral ischemia, depending on its localization and extent, secondary neuronal damage may occur that is remote from the initial lesion. In this study differences in secondary damage of the ventroposterior thalamic nucleus (VPN) and the reticular thalamic nucleus (RTN) were investigated with the use of different ischemia models. METHODS: Transient middle cerebral artery occlusion (MCAO) leads to cortical infarction, including parts of the basal ganglia such as the globus pallidus, and to widespread edema. Photothrombotic ischemia generates pure cortical infarcts sparing the basal ganglia and with only minor edema. Neuronal degeneration was quantified within the ipsilateral RTN and VPN 14 days after ischemia. Glial reactions were studied with the use of immunohistochemistry. RESULTS: MCAO resulted in delayed neuronal cell loss of the ipsilateral VPN and RTN. Glial activation occurred in both nuclei beginning after 24 hours. Photothrombotic ischemia resulted in delayed neuronal cell loss only within the VPN. Even 2 weeks after photothrombotic ischemia, glial activation could only be seen within the VPN. CONCLUSIONS: Pure cortical infarcts after photothrombotic ischemia, without major edema and without effects on the globus pallidus of the basal ganglia, only lead to secondary VPN damage that is possibly due to retrograde degeneration. MCAO, which results in infarction of cortex and globus pallidus and which causes widespread edema, leads to secondary damage in the VPN and RTN. Thus, additional RTN damage may be due to loss of protective GABAergic input from the globus pallidus to the RTN or due to the extensive edema. Retrograde degeneration is not possible because the RTN, in contrast to the VPN, has no efferents to the cortex.

Species-dependent differences of embryonic stem cell-derived neural stem cells after Interferon gamma treatment.

Pluripotent stem cell (pSC)-derived, neural stem cells (NSCs) are actually extensively explored in the field of neuroregeneration and to clarify disease mechanisms or model neurological diseases in vitro. Regarding the latter, proliferation and differentiation of pSC-derived NSCs are investigated under the influence of a variety of different substances among them key players of inflammation. However, results generated on a murine genetic background are not always representative for the human situation which increasingly leads to the application of human cell culture systems derived from human pSCs. We investigated here, if the recently described interferon gamma (IFNγ)-induced dysregulated neural phenotype characterized by simultaneous expression of glial and neuronal markers on murine NSCs (Walter et al., 2011, 2012) can also be found on a human genetic background. For this purpose, we performed experiments with human embryonic stem cell-derived NSCs. We could show that the IFNγ-induced dysregulated neural phenotype cannot be induced in human NSCs. This difference occurs, although typical genes like signal transducers and activators of transcription 1 (Stat 1) or interferon regulatory factor 9 (IRF-9) are similarly regulated by IFNγ in both, murine and human populations. These results illustrate that fundamental differences between murine and human neural populations exist in vitro, independent of anatomical system-related properties.