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Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular characteristics of the scar, very little is known about its mechanical properties. Here we characterize spatiotemporal changes of the elastic stiffness of the injured rat neocortex and spinal cord at 1.5 and three weeks post-injury using atomic force microscopy. In contrast to scars in other mammalian tissues, CNS tissue significantly softens after injury. Expression levels of glial intermediate filaments (GFAP, vimentin) and extracellular matrix components (laminin, collagen IV) correlate with tissue softening. As tissue stiffness is a regulator of neuronal growth, our results may help to understand why mammalian neurons do not regenerate after injury. Glial scars are thought to provide a biochemical and mechanical barrier to neuronal regeneration post-injury, but the mechanical properties of the scars have not been studied in detail. Here the authors perform atomic force microscopy measurements of glial scars from the injured rat cortex and spinal cord, and find that brain tissue softens in response to the injury.

Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1 +  myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies. The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness.

Hattori et al . review the recent advances in our understanding of the roles of inhibitory neuron subtypes in shaping the activity and plasticity states of neocortical circuits, how neuromodulators control inhibitory neuron subtypes, and the role of inhibitory neuron dysfunction in neurological disorders. Neocortical inhibitory neurons exhibit remarkably diverse morphology, physiological properties and connectivity. Genetic access to molecularly defined subtypes of inhibitory neurons has aided their functional characterization in recent years. These studies have established that, instead of simply balancing excitatory neuron activity, inhibitory neurons actively shape excitatory circuits in a subtype-specific manner. We review the emerging view that inhibitory neuron subtypes perform context-dependent modulation of excitatory activity, as well as regulate experience-dependent plasticity of excitatory circuits. We then review the roles of neuromodulators in regulating the subtype-specific functions of inhibitory neurons. Finally, we discuss the idea that dysfunctions of inhibitory neuron subtypes may be responsible for various aspects of neurological disorders.

Key Points The subplate zone is a highly dynamic structure that contains diverse cell populations that are derived from cortical (ventricular and subventricular zones) and extracortical (rostro-medial telencephalic wall and ganglionic eminence) sources. Interneurons may be underrepresented in the postnatal subplate. Subplate cells in rodents and primates share similarities, such as an early birth date and their location below the cortical plate, but they exhibit marked differences in relative cell survival times, molecular expression profiles and cell morphologies. Subplate cells pioneer axonal projections from the cortex to subcortical targets, but there are species differences in the targets that they innervate. Ablation of the subplate by excitotoxicity or immunotoxicity impairs circuit-level maturation of the primary sensory cortex, and an absence of subplate neurons prevents thalamic afferents from crossing the pallial–subpallial boundary and invading the cortex. Transcriptomic evidence highlights the relative maturity of embryonic and fetal subplate cells and suggests novel roles for subplate neurons in the secretion of various extracellular molecules involved in axon pathfinding, cell survival or differentiation, and synaptic plasticity. Histological, MRI and transcriptomic evidence points towards a role for the subplate in schizophrenia and autism. Whether this is causal or a consequence of earlier malformations remains unclear. The subplate is a transient cortical zone that forms during mammalian brain development and has a crucial role in the formation of intracortical and extracortical circuits. Here, Hoerder-Suabedissen and Molnár review the changing architecture and cellular diversity of this zone in developing mouse and primate brains. Subplate neurons have an essential role in cortical circuit formation. They are among the earliest formed neurons of the cerebral cortex, are located at the junction of white and grey matter, and are necessary for correct thalamocortical axon ingrowth. Recent transcriptomic studies have provided opportunities for monitoring and modulating selected subpopulations of these cells. Analyses of mouse lines expressing reporter genes have demonstrated novel, extracortical subplate neurogenesis and have shown how subplate cells are integrated under the influence of sensory activity into cortical and extracortical circuits. Recent studies have revealed that the subplate is involved in neurosecretion and modification of the extracellular milieu.

Haploinsufficiency of the voltage-gated sodium channel Na V1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of Na V1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the Na V1.1 sodium channel, Scn1a , revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome.

Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

The role of different cell types and their interactions in Alzheimer’s disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia. By inferring the cellular landscape of the neocortex in 638 aged individuals from RNA profiles, the authors uncovered unique cellular communities composed of coordinated populations of multiple cell types, which were altered in Alzheimer’s disease.

STXBP1 and SCN2A gene mutations are observed in patients with epilepsies, although the circuit basis remains elusive. Here, we show that mice with haplodeficiency for these genes exhibit absence seizures with spike-and-wave discharges (SWDs) initiated by reduced cortical excitatory transmission into the striatum. Mice deficient for Stxbp1 or Scn2a in cortico-striatal but not cortico-thalamic neurons reproduce SWDs. In Stxbp1 haplodeficient mice, there is a reduction in excitatory transmission from the neocortex to striatal fast-spiking interneurons (FSIs). FSI activity transiently decreases at SWD onset, and pharmacological potentiation of AMPA receptors in the striatum but not in the thalamus suppresses SWDs. Furthermore, in wild-type mice, pharmacological inhibition of cortico-striatal FSI excitatory transmission triggers absence and convulsive seizures in a dose-dependent manner. These findings suggest that impaired cortico-striatal excitatory transmission is a plausible mechanism that triggers epilepsy in Stxbp1 and Scn2a haplodeficient mice. Spike and wave discharge (SWD) activity is seen during absence seizures and is thought to be thalamocortical in origin. Here, the authors show that SWDs are initiated through the impaired corticostriatal excitatory transmissions onto striatal fast spiking interneurons.

Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause familial hemiplegic migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain of function to CSD generation in FHM3. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.

Tau neurofibrillary tangles (NFTs) in the presence of amyloid-β (Aβ) plaques are required for the diagnosis of Alzheimer’s Disease (AD) and closely track with cognitive impairment, yet cognitively normal aged individuals frequently exhibit NFTs arising from tau seed accumulation. This may suggest that not all tau species are equally pathogenic and raises the question of whether unidentified tau modifications augment tau seeding activity and neurodegeneration in AD. We investigated how biochemical modifications of tau relate to clinicopathological outcomes in a cohort of 38 patients with Braak-matched AD neuropathologic change (ADNC) or primary age-related tauopathy (PART), a 3R/4R tauopathy with identical tau filament core structure to ADNC but with little to no Aβ deposition. We comprehensively measured tau histologic density, seeding activity using real-time quaking induced conversion (RT-QuIC) seed amplification assays, and select post-translational modifications (PTMs) (i.e. pT217, pS202/T205, & C-terminal epitopes) in hippocampus and neocortex. Even in cases without overt neocortical tau neuropathology, substantial hippocampal and neocortical tau seeding occurred in both PART and ADNC and predicted region-specific cognitive performance and longitudinal decline. Notably, tau seeding and PTM profiles were associated with Aβ neuritic plaque density and differentiated ADNC from PART in neocortex. Our data indicate that tau seed modifications meaningfully relate to disease trajectory, potentially explaining the more severe cognitive dysfunction observed in late-stage AD versus PART. Abnormal, misfolded tau proteins are found in cognitively normal individuals and Tauopathies, suggesting not all tau species are pathogenic. Here, the authors show tau seeding and post-translational modification profiles were associated with Aβ neuritic plaque density and differentiated two tauopathies.