Cortical assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects.

Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during brain development remains poorly understood. The protracted maturation of these cells during postnatal life has made their derivation from human pluripotent stem cells (hPSCs) extremely difficult, precluding hPSC-based disease modeling of their role in neuropsychiatric disease.

An in vitro model of neuronal ensembles.

Advances in 3D neuronal cultures, such as brain spheroids and organoids, are allowing unprecedented in vitro access to some of the molecular, cellular and developmental mechanisms underlying brain diseases. However, their efficacy in recapitulating brain network properties that encode brain function remains limited, thereby precluding development of effective in vitro models of complex brain disorders like schizophrenia. Here, we develop and characterize a Modular Neuronal Network (MoNNet) approach that recapitulates specific features of neuronal ensemble dynamics, segregated local-global network activities and a hierarchical modular organization.

Vascular-derived SPARC and SerpinE1 regulate interneuron tangential migration and accelerate functional maturation of human stem cell-derived interneurons.

Cortical interneurons establish inhibitory microcircuits throughout the neocortex and their dysfunction has been implicated in epilepsy and neuropsychiatric diseases. Developmentally, interneurons migrate from a distal progenitor domain in order to populate the neocortex - a process that occurs at a slower rate in humans than in mice. In this study, we sought to identify factors that regulate the rate of interneuron maturation across the two species.

Recapitulation and Reversal of Schizophrenia-Related Phenotypes in Setd1a-Deficient Mice.

SETD1A, a lysine-methyltransferase, is a key schizophrenia susceptibility gene. Mice carrying a heterozygous loss-of-function mutation of the orthologous gene exhibit alterations in axonal branching and cortical synaptic dynamics accompanied by working memory deficits. We show that Setd1a binds both promoters and enhancers with a striking overlap between Setd1a and Mef2 on enhancers.

The abiding relevance of mouse models of rare mutations to psychiatric neuroscience and therapeutics.

Studies using powerful family-based designs aided by large scale case-control studies, have been instrumental in cracking the genetic complexity of the disease, identifying rare and highly penetrant risk mutations and providing a handle on experimentally tractable model systems. Mouse models of rare mutations, paired with analysis of homologous cognitive and sensory processing deficits and state-of-the-art neuroscience methods to manipulate and record neuronal activity have started providing unprecedented insights into pathogenic mechanisms and building the foundation of a new biological framework for understanding mental illness. A number of important principles are emerging, namely that degradation of the computational mechanisms underlying the ordered activity and plasticity of both local and long-range neuronal assemblies, the building blocks necessary for stable cognition and perception, might be the inevitable consequence and the common point of convergence of the vastly heterogeneous genetic liability, manifesting as defective internally- or stimulus-driven neuronal activation patterns and triggering the constellation of schizophrenia symptoms.

Role of Endogenous Metabolite Alterations in Neuropsychiatric Disease.

The potential role in neuropsychiatric disease risk arising from alterations and derangements of endogenous small-molecule metabolites remains understudied. Alterations of endogenous metabolite concentrations can arise in multiple ways. Marked derangements of single endogenous small-molecule metabolites are found in a large group of rare genetic human diseases termed "inborn errors of metabolism", many of which are associated with prominent neuropsychiatric symptomology.

Alteration of Neuronal Excitability and Short-Term Synaptic Plasticity in the Prefrontal Cortex of a Mouse Model of Mental Illness.

Using a genetic mouse model that faithfully recapitulates a genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V.

Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.

Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders.

Synaptic plasticity, neural circuits, and the emerging role of altered short-term information processing in schizophrenia.

Synaptic plasticity alters the strength of information flow between presynaptic and postsynaptic neurons and thus modifies the likelihood that action potentials in a presynaptic neuron will lead to an action potential in a postsynaptic neuron. As such, synaptic plasticity and pathological changes in synaptic plasticity impact the synaptic computation which controls the information flow through the neural microcircuits responsible for the complex information processing necessary to drive adaptive behaviors. As current theories of neuropsychiatric disease suggest that distinct dysfunctions in neural circuit performance may critically underlie the unique symptoms of these diseases, pathological alterations in synaptic plasticity mechanisms may be fundamental to the disease process.

Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1.

We previously identified lynx1 as a neuronal membrane molecule related to snake alpha-neurotoxins able to modulate nAChRs. Here, we show that lynx1 colocalizes with nAChRs on CNS neurons and physically associates with nAChRs. Single-channel recordings show that lynx1 promotes the largest of three current amplitudes elicited by ACh through alpha(4)beta(2) nAChRs and that lynx1 enhances desensitization.