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MYT1L is an autism spectrum disorder (ASD)-associated transcription factor that is expressed in virtually all neurons throughout life. How MYT1Lmutations cause neurological phenotypes and whether they can be targeted remains enigmatic. Here, we examine the effects of MYT1L deficiency in human neurons and mice. Mutant mice exhibit neurodevelopmental delays with thinner cortices, behavioural phenotypes, and gene expression changes that resemble those of ASD patients. MYT1L target genes, including WNTand NOTCH, are activated upon MYT1L depletion and their chemical inhibition can rescue delayed neurogenesis in vitro. MYT1L deficiency also causes upregulation of the main cardiac sodium channel, SCN5A, and neuronal hyperactivity, which could be restored by shRNA-mediated knockdown of SCN5Aor MYT1Loverexpression in postmitotic neurons. Acute application of the sodium channel blocker, lamotrigine, also rescued electrophysiological defects in vitro and behaviour phenotypes in vivo. Hence, MYT1Lmutation causes both developmental and postmitotic neurological defects. However, acute intervention can normalise resulting electrophysiological and behavioural phenotypes in adulthood.

The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance1–3. Here, we show that antigen-specific avoidance behaviour in inbred mice4,5is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.

In mammals, most adult neural stem cells (NSCs) are located in the ventricular–subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior–ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.

It is still widely thought that cortical projections to distant brain areas derive by and large from glutamatergic neurons. However, an increasing number of reports provide evidence that cortical GABAergic neurons comprise a smaller population of ‘projection neurons’ in addition to the well-known and much-studied interneurons. GABAergic long-range axons that derive from, or project to, cortical areas are thought to entrain distant brain areas for efficient information transfer and processing. Research conducted over the past 10 years has revealed that cortical GABAergic projection neurons are highly diverse in terms of molecular marker expression, synaptic targeting (identity of targeted cell types), activity pattern during distinct behavioural states and precise temporal recruitment relative to ongoing neuronal network oscillations. As GABAergic projection neurons connect many cortical areas unidirectionally or bidirectionally, it is safe to assume that they participate in the modulation of a whole series of behavioural and cognitive functions. We expect future research to examine how long-range GABAergic projections fine-tune activity in distinct distant networks and how their recruitment alters the behaviours that are supported by these networks.

The establishment of neuronal and glial networks in the brain depends on the activities of neural progenitors, which are influenced by cell-intrinsic mechanisms, interactions with the local microenvironment and long-range signaling. Progress in neuroscience has helped identify key factors in CNS development. In parallel, studies in recent years have increased our understanding of molecular and cellular factors in the development and growth of primary brain tumors. To thrive, glioma cells exploit pathways that are active in normal CNS progenitor cells, as well as in normal neurotransmitter signaling. Furthermore, tumor cells of incurable gliomas integrate into communicating multicellular networks, where they are interconnected through neurite-like cellular protrusions. In this Review, we discuss evidence that CNS development, organization and function share a number of common features with glioma progression and malignancy. These include mechanisms used by cells to proliferate and migrate, interact with their microenvironment and integrate into multicellular networks. The emerging intersections between the fields of neuroscience and neuro-oncology considered in this review point to new research directions and novel therapeutic opportunities.

Path integration (PI) is a highly conserved, self-motion-based navigation strategy. Since the discovery of grid cells in the medial entorhinal cortex, neurophysiological data and computational models have suggested that these neurons serve PI. However, more direct empirical evidence supporting this hypothesis has been missing due to a lack of selective manipulations of grid cell activity and suitable behavioral assessments. Here we report that selective disruption of grid cell activity in mice can be achieved by removing NMDA glutamate receptors from the retro-hippocampal region and that disrupted grid cell firing accounts for impaired PI performance. Notably, the genetic manipulation did not affect the activity of other spatially selective cells in the medial entorhinal cortex and the hippocampus. By directly linking grid cell activity to PI, these results contribute to a better understanding of how grid cells support navigation and spatial memory. Grid cell activity may subserve path integration, but a direct link is lacking. The authors selectively disrupt retro-hippocampal region grid cell activity and show that disrupted grid cell firing impairs performance in a path integration task.

The motor cortico-basal ganglion loop is critical for motor planning, execution, and learning. Balanced excitation and inhibition in this loop is crucial for proper motor output. Excitatory neurons have been thought to be the only source of motor cortical input to the striatum. Here, we identify long-range projecting GABAergic neurons in the primary (M1) and secondary (M2) motor cortex that target the dorsal striatum. This population of projecting GABAergic neurons comprises both somatostatin-positive (SOM+) and parvalbumin-positive (PV+) neurons that target direct and indirect pathway striatal output neurons as well as cholinergic interneurons differentially. Notably, optogenetic stimulation of M1 PV+and M2 SOM+projecting neurons reduced locomotion, whereas stimulation of M1 SOM+projecting neurons enhanced locomotion. Thus, corticostriatal GABAergic projections modulate striatal output and motor activity.

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The lateral entorhinal cortex (LEC) computes and transfers olfactory information from the olfactory bulb to the hippocampus. Here we established LEC connectivity to upstream and downstream brain regions to understand how the LEC processes olfactory information. We report that, in layer II (LII), reelin- and calbindin-positive (RE+and CB+) neurons constitute two major excitatory cell types that are electrophysiologically distinct and differentially connected. RE+neurons convey information to the hippocampus, while CB+neurons project to the olfactory cortex and the olfactory bulb. In vivo calcium imaging revealed that RE+neurons responded with higher selectivity to specific odors than CB+neurons and GABAergic neurons. At the population level, odor discrimination was significantly better for RE+than CB+neurons, and was lowest for GABAergic neurons. Thus, we identified in LII of the LEC anatomically and functionally distinct neuronal subpopulations that engage differentially in feedforward and feedback signaling during odor processing.

AMPA -Rezeptoren sind ionotrope Glutamat- Rezeptoren, die für einen großen Teil der schnellen Exzitation im zentralen Nervensystem verantwortlich sind. Ihre Funktion wird uber die Zusammensetzung aus den Untereinheiten GluA1-4, aber auch über Interaktion mit auxiliären Untereinheiten moduliert. In den letzten Jahren hat man durch Proteomanalysen eine Reihe an neuen auxiliären Untereinheiten identifiziert und beginnt, die komplexe Kontrolle der physiologischen Eigenschaften und des Membrantransportes der AMPA -Rezeptoren über diese Proteine zu verstehen. Auxiliäre Untereinheiten wie TARPs, Cornichons und CKAMP44 beeinflussen die Lokalisation der Rezeptoren auf der Zellmembran, modulieren deren Stromeigenschaften und spielen eine Rolle bei synaptischer Kurzzeit- und Langzeitplastizität.

AMPA receptors are ionotropic glutamate receptors that mediate the majority of fast excitatory transmission in the central nervous system. Their function depends not only on the composition of the subunits GluA1-4, but also on the interaction with auxiliary subunits. Several auxiliary subunits have been identified in proteomic analyses over the last years and we are beginning to understand the complex control of these proteins on physiological properties and membrane- transport of AMPA receptors. Auxiliary subunits such as TARPs, cornichons, and CK-AMP44 influence receptor localization on the cell membrane, modulate receptor gating, and play a role for synaptic short-term and long-term plasticity.

The dentate gyrus (DG) receives substantial input from the homologous brain area of the contralateral hemisphere. This input is by and large excitatory. Viral-tracing experiments provided anatomical evidence for the existence of GABAergic connectivity between the two DGs, but the function of these projections has remained elusive. Combining electrophysiological and optogenetic approaches, we demonstrate that somatostatin-expressing contralateral DG (SOM+cDG)-projecting neurons preferentially engage dendrite-targeting interneurons over principal neurons. Single-unit recordings from freely moving mice reveal that optogenetic stimulation of SOM+cDG projections modulates the activity of GABAergic neurons and principal neurons over multiple timescales. Importantly, we demonstrate that optogenetic silencing of SOM+cDG projections during spatial memory encoding, but not during memory retrieval, results in compromised DG-dependent memory. Moreover, optogenetic stimulation of SOM+cDG projections is sufficient to disrupt contextual memory recall. Collectively, our findings reveal that SOM+long-range projections mediate inter-DG inhibition and contribute to learning and memory.

Downregulation of the schizophrenia-associated gene DISC1and its interacting protein FEZ1 positively regulates dendrite growth in young neurons. However, little is known about the mechanism that controls these molecules during neuronal development. Here, we identify several components of the ubiquitin proteasome system and the cell-cycle machinery that act upstream of FEZ1. We demonstrate that the ubiquitin ligase cell division cycle 20/anaphase-promoting complex (Cdc20/APC) controls dendrite growth by regulating the degradation of FEZ1. Furthermore, dendrite growth is modulated by BubR1, whose known function so far has been restricted to control Cdc20/APC activity during the cell cycle. The modulatory function of BubR1 is dependent on its acetylation status. We show that BubR1 is deacetylated by Hdac11, thereby disinhibiting the Cdc20/APC complex. Because dendrite growth is affected both in hippocampal dentate granule cells and olfactory bulb neurons upon modifying expression of these genes, we conclude that the proposed mechanism governs neuronal development in a general fashion.

Pannexin (Px, Panx) channels have been implicated in several physiological and pathological processes. We recently studied the potential contribution of pannexins in ischemic brain damage using Px1-/-Px2-/-mice and provided evidence that (1) the release of IL-1β and hemichannel function in astrocytes are, in contrast to published data, not affected by the absence of Px1 and Px2, (2) channel function in neurons lacking Px1 and Px2 is impaired and (3) Px1-/-Px2-/-mice had a better functional outcome and smaller infarcts than wild-type mice when subjected to ischemic stroke. Here, we further investigate the neurological outcome of wild-type and pannexin double-knockout mice 48 h after permanent occlusion of the distal middle cerebral artery (MCAO). Pannexin double-knockout mice (Px1-/-Px2-/-) were less impaired in parameters such as exploration, anxiety, sensorimotor function and behavioral symmetry.

The subventricular zone (SVZ) of the lateral ventricles is the largest neurogenic niche of the postnatal brain. New SVZ-generated neurons migrate via the rostral migratory stream to the olfactory bulb (OB) where they functionally integrate into preexisting neuronal circuits. Nonsynaptic GABA signaling was previously shown to inhibit SVZ-derived neurogenesis. Here we identify the endogenous protein diazepam binding inhibitor (DBI) as a positive modulator of SVZ postnatal neurogenesis by regulating GABA activity in transit-amplifying cells. We performed DBI loss- and gain-of-function experiments in vivo at the peak of postnatal OB neuron generation in mice and demonstrate that DBI enhances proliferation by preventing SVZ progenitors to exit the cell cycle. Furthermore, we provide evidence that DBI exerts its effect on SVZ progenitors via its octadecaneuropeptide proteolytic product (ODN) by inhibiting GABA-induced currents. Together our data reveal a regulatory mechanism by which DBI counteracts the inhibitory effect of nonsynaptic GABA signaling on subventricular neuronal proliferation.

Hemichannels are transmembrane channels that represent the functional subunits of gap junctions. Each hemichannel is composed of a connexin or pannexin hexamer and, after being transported to the membrane, remains unpaired until it is incorporated in a gap junction. Several studies have already provided evidence that gap junction-mediated intercellular diffusion of ions and small molecules during ischemia represents an important mechanism through which necrotic, apoptotic, or even protective signals are transported between cells. Although initially hemichannels were supposed to be functional only in gap junctions, recent findings indicate that unpaired hemichannels also display a large array of activities that can be modulated under several pathophysiological conditions, including ischemia. Open hemichannels in ischemia dramatically alter the permeability properties of membranes and lead to cell death through ionic dysregulation, loss of metabolites, and changes in intracellular ATP. This review focuses on the properties and possible functions of unpaired connexin and pannexin hemichannels and the implications this has for a variety of events, such as cell death, glutamate release, oxidative stress, cortical spreading depression, that occur during an ischemic insult and may affect its outcome.

Direct cell-to-cell communication through specialized intercellular channels is a characteristic feature of virtually all multi-cellular organisms. The remarkable functional conservation of cell-to-cell coupling throughout the animal kingdom, however, is not matched at the molecular level of the structural protein components. Thus protostomes (including nematodes and flies) and deuterostomes (including all vertebrates) utilize two unrelated families of gap-junction genes, innexins and connexins, respectively. The recent discovery that pannexins, a novel group of proteins expressed by several organisms, are able to form intercellular channels has started a quest to understand their evolutionary relationship and functional contribution to cell communication in vivo. There are three pannexin genes in mammals, two of which are co-expressed in the developing and adult brain. Of note, pannexin1 can also form Ca2+-activated hemichannels that open at physiological extracellular Ca2+concentrations and exhibit distinct pharmacological properties.

Direct cell-to-cell communication through specialized intercellular channels is a characteristic feature of virtually all multi-cellular organisms. The remarkable functional conservation of cell-to-cell coupling throughout the animal kingdom, however, is not matched at the molecular level of the structural protein components. Thus protostomes (including nematodes and flies) and deuterostomes (including all vertebrates) utilize two unrelated families of gap-junction genes, innexins and connexins, respectively. The recent discovery that pannexins, a novel group of proteins expressed by several organisms, are able to form intercellular channels has started a quest to understand their evolutionary relationship and functional contribution to cell communication in vivo. There are three pannexin genes in mammals, two of which are co-expressed in the developing and adult brain. Of note, pannexin1 can also form Ca2+-activated hemichannels that open at physiological extracellular Ca2+ concentrations and exhibit distinct pharmacological properties.

The binding site for the co-agonist glycine onN-methyl-d-aspartate (NMDA) receptors has been mapped to the NR1 subunit whereas binding of the principal agonist glutamate is mediated by the NR2 subunits. Using the novel glycine site antagonist and photoaffinity label CGP 61594, distinct contributions of the NR2 subunit variants to the glycine antagonist binding domains of NMDA receptor subtypes are demonstrated. High affinity sites for CGP 61594 were exclusively displayed by NR1/2B receptors, as shown by their co-distribution with the NR2B subunit, by subunit-selective immunoprecipitation and by functional analysis of NR1/2B receptors expressed in Xenopusoocytes (inhibitory potency, IC50= 45 ± 11 nm). Other NMDA receptor subtypes are clearly distinguished by reduced inhibitory potencies for CGP 61594, being low for NR1/2A and NR1/2D receptors (IC50= 430 ± 105 nmand 340 ± 61 nm, respectively) and intermediate for NR1/2C receptors (IC50= 164 ± 27 nm). Glycine antagonist sites with low and intermediate affinity for [3H]CGP 61594 were detected also in situby radioligand binding in brain areas predominantly expressing the NR2A and NR2C subunits, respectively. Thus, [3H]CGP 61594 is the first antagonist radioligand that reliably distinguishes the glycine site of NMDA receptor subtypes. [3H]CGP 61594 is a promising tool to identify the NR2 subunit domains that contribute to differential glycine antagonist sites of NMDA receptor subtypes.

Septal parvalbumin-expressing (PV+) and calbindin-expressing (CB+) projections inhibit low-threshold and fast-spiking interneurons, respectively, in the medial entorhinal cortex (MEC). We investigate how the two inputs control neuronal activity in the MEC in freely moving mice. Stimulation of PV+and CB+terminals causes disinhibition of spatially tuned MEC neurons, but exerts differential effects on temporal coding and burst firing. Thus, recruitment of PV+projections disrupts theta-rhythmic firing of MEC neurons, while stimulation of CB+projections increases burst firing of grid cells and enhances phase precession in a cell-type-specific manner. Inactivation of septal PV+or CB+neurons differentially affects context, reference, and working memory. Together, our results reveal how specific connectivity of septal GABAergic projections with MEC interneurons translates into differential modulation of MEC neuronal coding.

Up-down states (UDS) are synchronous cortical events of neuronal activity during non-REM sleep. The medial entorhinal cortex (MEC) exhibits robust UDS during natural sleep and under anesthesia. However, little is known about the generation and propagation of UDS-related activity in the MEC. Here, we dissect the circuitry underlying UDS generation and propagation across layers in the MEC using both in vivoand in vitroapproaches. We provide evidence that layer 3 (L3) MEC is crucial in the generation and maintenance of UDS in the MEC. Furthermore, we find that the two sublayers of the L5 MEC participate differentially during UDS. Our findings show that L5b, which receives hippocampal output, is strongly innervated by UDS activity originating in L3 MEC. Our data suggest that L5b acts as a coincidence detector during information transfer between the hippocampus and the cortex and thereby plays an important role in memory encoding and consolidation.

We report the direct reprogramming of both adult human fibroblasts and blood cells into induced neural plate border stem cells (iNBSCs) by ectopic expression of four neural transcription factors. Self-renewing, clonal iNBSCs can be robustly expanded in defined media while retaining multilineage differentiation potential. They generate functional cell types of neural crest and CNS lineages and could be used to model a human pain syndrome via gene editing of SCN9A in iNBSCs. NBSCs can also be derived from human pluripotent stem cells and share functional and molecular features with NBSCs isolated from embryonic day 8.5 (E8.5) mouse neural folds. Single-cell RNA sequencing identified the anterior hindbrain as the origin of mouse NBSCs, with human iNBSCs sharing a similar regional identity. In summary, we identify embryonic NBSCs and report their generation by direct reprogramming in human, which may facilitate insights into neural development and provide a neural stem cell source for applications in regenerative medicine.