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. Using embryonic mouse development as a model system, we found that the process of initiating interneuron migration is regulated by blood vessels of the medial ganglionic eminence (MGE), an interneuron progenitor domain. We identified two endothelial cell-derived paracrine factors, SPARC and SerpinE1, that enhance interneuron migration in mouse MGE explants and organotypic cultures. Moreover, pre-treatment of human stem cell-derived interneurons (hSC-interneurons) with SPARC and SerpinE1 prior to transplantation into neonatal mouse cortex enhanced their migration and morphological elaboration in the host cortex. Further, SPARC and SerpinE1-treated hSC-interneurons also exhibited more mature electrophysiological characteristics compared to controls. Overall, our studies suggest a critical role for CNS vasculature in regulating interneuron developmental maturation in both mice and humans.

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. Setd1a targets are highly expressed in pyramidal neurons and display a complex pattern of transcriptional up- and downregulations shaped by presumed opposing functions of Setd1a on promoters and Mef2-bound enhancers. Notably, evolutionarily conserved Setd1a targets are associated with neuropsychiatric genetic risk burden. Reinstating Setd1a expression in adulthood rescues cognitive deficits. Finally, we identify LSD1 as a major counteracting demethylase for Setd1a and show that its pharmacological antagonism results in a full rescue of the behavioral and morphological deficits in Setd1a-deficient mice. Our findings advance understanding of how SETD1A mutations predispose to schizophrenia (SCZ) and point to novel therapeutic interventions.

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. Whether such metabolites act neuroactively to directly lead to distinct neural dysfunction has been frequently hypothesized but rarely demonstrated unequivocally. Here we discuss this disease concept in the context of our recent findings demonstrating that neural dysfunction arising from accumulation of the schizophrenia-associated metabolite l-proline is due to its structural mimicry of the neurotransmitter GABA that leads to alterations in GABA-ergic short-term synaptic plasticity. For cases in which a similar direct action upon neurotransmitter binding sites is suspected, we lay out a systematic approach that can be extended to assessing the potential disruptive action of such candidate disease metabolites. To address the potentially important and broader role in neuropsychiatric disease, we also consider whether the more subtle yet more ubiquitous variations in endogenous metabolites arising from natural allelic variation may likewise contribute to disease risk but in a more complex and nuanced manner.

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 DISC1 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. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit Kv1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of Kv1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.SIGNIFICANCE STATEMENT Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes, DISC1, upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity-parameters that critically govern neural circuit information processing-suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.

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. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.

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. Here we consider mechanisms of both short-term and long-term plasticity of synaptic transmission and their possible roles in information processing by neural microcircuits in both health and disease. As paradigms of neuropsychiatric diseases with strongly implicated risk genes, we discuss the findings in schizophrenia and autism and consider the alterations in synaptic plasticity and network function observed in both human studies and genetic mouse models of these diseases. Together these studies have begun to point toward a likely dominant role of short-term synaptic plasticity alterations in schizophrenia while dysfunction in autism spectrum disorders (ASDs) may be due to a combination of both short-term and long-term synaptic plasticity alterations.

The 22q11.2 microdeletion: fifteen years of insights into the genetic and neural complexity of psychiatric disorders.

Over the last fifteen years it has become established that 22q11.2 deletion syndrome (22q11DS) is a true genetic risk factor for schizophrenia. Carriers of deletions in chromosome 22q11.2 develop schizophrenia at rate of 25-30% and such deletions account for as many as 1-2% of cases of sporadic schizophrenia in the general population. Access to a relatively homogeneous population of individuals that suffer from schizophrenia as the result of a shared etiological factor and the potential to generate etiologically valid mouse models provides an immense opportunity to better understand the pathobiology of this disease. In this review we survey the clinical literature associated with the 22q11.2 microdeletions with a focus on neuroanatomical changes. Then, we highlight results from work modeling this structural mutation in animals. The key biological pathways disrupted by the mutation are discussed and how these changes impact the structure and function of neural circuits is described.

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. Macroscopic recordings quantify the enhancement of desensitization onset by lynx1 and further show that it slows recovery from desensitization and increases the EC(50). These experiments establish that direct interaction of lynx1 with nAChRs can result in a novel type of functional modulation and suggest that prototoxins may play important roles in vivo by modulating functional properties of their cognate CNS receptors.