Typical development of synaptic and neuronal properties can proceed without microglia in the cortex and thalamus.

Brain-resident macrophages, microglia, have been proposed to have an active role in synaptic refinement and maturation, influencing plasticity and circuit-level connectivity. Here we show that several neurodevelopmental processes previously attributed to microglia can proceed without them. Using a genetically modified mouse that lacks microglia (Csf1r), we find that intrinsic properties, synapse number and synaptic maturation are largely normal in the hippocampal CA1 region and somatosensory cortex at stages where microglia have been implicated.

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology.

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency.

Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons.

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes.

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3 rat model of autism.

Background: Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3.

Transactive response DNA-binding protein-43 proteinopathy in oligodendrocytes revealed using an induced pluripotent stem cell model.

Oligodendrocytes are implicated in amyotrophic lateral sclerosis pathogenesis and display transactive response DNA-binding protein-43 (TDP-43) pathological inclusions. To investigate the cell autonomous consequences of TDP-43 mutations on human oligodendrocytes, we generated oligodendrocytes from patient-derived induced pluripotent stem cell lines harbouring mutations in the gene, namely G298S and M337V. Through a combination of immunocytochemistry, electrophysiological assessment via whole-cell patch clamping, and three-dimensional cultures, no differences in oligodendrocyte differentiation, maturation or myelination were identified.

Antagonistic postsynaptic and presynaptic actions of cyclohexanol on neuromuscular synaptic transmission and function.

Intentional ingestion of agricultural organophosphorus insecticides is a significant public health issue in rural Asia, causing thousands of deaths annually. Some survivors develop a severe, acute or delayed myasthenic syndrome. In animal models, similar myasthenia has been associated with increasing plasma concentration of one insecticide solvent metabolite, cyclohexanol.

Correction of amygdalar dysfunction in a rat model of fragile X syndrome.

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS.

21st century excitatory amino acid research: A Q & A with Jeff Watkins and Dick Evans.

In 1981 Jeff Watkins and Dick Evans wrote what was to become a seminal review on excitatory amino acids (EAAs) and their receptors (Watkins and Evans, 1981). Bringing together various lines of evidence dating back over several decades on: the distribution in the nervous system of putative amino acid neurotransmitters; enzymes involved in their production and metabolism; the uptake and release of amino acids; binding of EAAs to membranes; the pharmacological action of endogenous excitatory amino acids and their synthetic analogues, and notably the actions of antagonists for the excitations caused by both nerve stimulation and exogenous agonists, often using pharmacological tools developed by Jeff and his colleagues, they provided a compelling account for EAAs, especially l-glutamate, as a bona fide neurotransmitter in the nervous system. The rest, as they say, is history, but far from being consigned to history, EAA research is in rude health well into the 21st Century as this series of Special Issues of Neuropharmacology exemplifies.

Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons.

The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus.

NMDA receptor function in inhibitory neurons.

N-methyl-d-aspartate receptors (NMDARs) are present in the majority of brain circuits and play a key role in synaptic information transfer and synaptic plasticity. A key element of many brain circuits are inhibitory GABAergic interneurons that in themselves show diverse and cell-type-specific NMDAR expression and function. Indeed, NMDARs located on interneurons control cellular excitation in a synapse-type specific manner which leads to divergent dendritic integration properties amongst the plethora of interneuron subtypes known to exist.

Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction.

Background: Physiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72) mutation - the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear.

Input-Output Relationship of CA1 Pyramidal Neurons Reveals Intact Homeostatic Mechanisms in a Mouse Model of Fragile X Syndrome.

Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. Here, we show increased axon initial segment length in CA1 of the Fmr1 mouse hippocampus, with increased cellular excitability.

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns.

Background: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP).

Altered dendritic spine function and integration in a mouse model of fragile X syndrome.

Cellular and circuit hyperexcitability are core features of fragile X syndrome and related autism spectrum disorder models. However, the cellular and synaptic bases of this hyperexcitability have proved elusive. We report in a mouse model of fragile X syndrome, glutamate uncaging onto individual dendritic spines yields stronger single-spine excitation than wild-type, with more silent spines.

Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex.

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development.

Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction.

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development.

The human NMDA receptor GluN2A variant influences channel blocker potency.

-methyl-D-aspartate (NMDA) receptors are glutamate receptors with key roles in synaptic plasticity, due in part to their Mg mediated voltage-dependence. A large number of genetic variants affecting NMDA receptor subunits have been found in people with a range of neurodevelopmental disorders, including GluN2A () in two unrelated individuals with severe epileptic encephalopathy. This missense variant substitutes a lysine in place of an asparagine known to be important for blockade by Mg and other small molecule channel blockers.

Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown.

In Vitro Generation and Electrophysiological Characterization of OPCs and Oligodendrocytes from Human Pluripotent Stem Cells.

The in vitro generation of defined cellular populations from induced human pluripotent stem cells (iPSCs) provides the opportunity to work routinely with human material and, importantly, allows examination of material derived from patients with clinically and genetically diagnosed disorders. In this regard, the ability to derive oligodendrocytes in vitro represents an important resource to examine human oligodendrocyte-lineage cell biology in normal and disease contexts. Oligodendrocytes undergo characteristic physiological maturation during differentiation in vitro, and patch-clamp electrophysiology allows a detailed examination of maturation state and, potentially, pathologically related variations of ion channel expression and regulation.

Functional assessment of triheteromeric NMDA receptors containing a human variant associated with epilepsy.

Key Points: NMDA receptors are neurotransmitter-gated ion channels that are critically involved in brain cell communication Variations in genes encoding NMDA receptor subunits have been found in a range of neurodevelopmental disorders. We investigated a de novo genetic variant found in patients with epileptic encephalopathy that changes a residue located in the ion channel pore of the GluN2A NMDA receptor subunit. We found that this variant (GluN2A ) impairs physiologically important receptor properties: it markedly reduces Mg blockade and channel conductance, even for receptors in which one GluN2A is co-assembled with one wild-type GluN2A subunit.

GRIN2A-related disorders: genotype and functional consequence predict phenotype.

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals.

Reversal of proliferation deficits caused by chromosome 16p13.11 microduplication through targeting NFκB signaling: an integrated study of patient-derived neuronal precursor cells, cerebral organoids and in vivo brain imaging.

The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.