Biology subjects

Macklis, J. D.

Publications and source records attributed to Macklis, J. D..

15 recordsLinked to original sources

bioRxiv2026

Sequestration of growth cone surface proteins by cytoplasmic Lrrtm2 induces de novo amygdala innervation by cerebral cortex associative neurons

Precise establishment of distinct cerebral cortex circuits is essential for sensorimotor function, high-level cognition, and cross-modality integration and association. Although an increasing set of molecular controls over subtype-specific cortical wiring have been identified, much less is known about how molecules in growth cones (GCs) regulate precise long-range projection of axons through complex environments, or how dysregulation of GC molecular machinery disrupts precision of circuit formation. Here, we discover a generalizable mechanism for regulation of precise circuit wiring by focusing on callosal projection neurons (CPN), which link cortical hemispheres via the corpus callosum. CPN are centrally involved in associative and cognitive function, and are often disrupted in people with autism spectrum disorders (ASD) and intellectual disabilities (ID). We identify dysregulated subcellular CPN GC proteomes in vivo after CPN-specific deletion of Bcl11a/Ctip1, a transcription factor (TF) with variants that cause ASD/ID in humans, and validate localization of dysregulated proteins to CPN GCs ex vivo. We identify that disruption of Lrrtm2 - a canonically postsynaptic transmembrane protein - in CPN GCs specifically induces de novo innervation of the amygdala, an evolutionarily ancient regulator of social behavior, cognition, and anxiety that is abnormally activated in humans with ASD. Mechanistically, we identify that deletion of Bcl11a from CPN disrupts targeting of Lrrtm2 to CPN GC membranes, causing cytoplasmic sequestration of key CPN GC surface proteins, and resulting in aberrant innervation of basolateral amygdala (BLA), which is typically targeted by evolutionarily older archicortex. Together, this work connects deletion of a causal ASD/ID TF, dysregulation of a non-canonical control over GC surface protein remodeling, and formation of a de novo, subtype-specific circuit between cerebral cortex and BLA - similar mechanisms likely generalize across neuron subtypes. These results expand conceptual understanding of how diverse circuits are precisely constructed and potentially evolve, and how coordinated dysregulation of GC molecules can disrupt precise subtype-specific circuitry, contributing to diverse neurodevelopmental and neuropsychiatric disorders.

neuroscience↗

bioRxiv2025

Developmental dynamics and axonal transport of cerebral cortex projection neuron mRNAs in vivo

Appropriate development of long-range nervous system circuitry requires dynamic regulation of subcellular mRNA localization, but little is known about how specific neuron subtypes control this critical process in vivo. Here, we employ an integrated genetic and temporally controlled approach to investigate in vivo developmental mRNA dynamics in somata and axons of a prototypical cerebral cortex projection neuron subtype, callosal projection neurons (CPN), which connect the cortical hemispheres to integrate sensorimotor information, and regulate high-level associative cognition and behavior. We identify cis-regulatory elements that are associated with mRNA turnover in CPN somata, including specific 3 untranslated regions (UTRs), and elucidate distinct modes of axon transport in CPN axons for function-specific mRNA classes. Together, these findings elucidate how developing CPN control subcellular mRNA localization, and how dysregulation of these processes might lead to neurodevelopmental and/or neurodegenerative disorders. More broadly, this work identifies general mRNA localization mechanisms that likely function across projection neuron subtypes, and in other polarized cells.

neuroscience↗

bioRxiv2024

Cortical projection neurons with distinct axonal connectivity employ ribosomal complexes with distinct protein compositions

Diverse subtypes of cortical projection neurons (PN) form long-range axonal projections that are responsible for distinct sensory, motor, cognitive, and behavioral functions. Translational control has been identified at multiple stages of PN development, but how translational regulation contributes to formation of distinct, subtype-specific long-range circuits is poorly understood. Ribosomal complexes (RCs) exhibit variations of their component proteins, with an increasing set of examples that confer specialized translational control. Here, we directly compare the protein compositions of RCs in vivo from two closely related cortical neuron subtypes-cortical output "subcerebral PN" (SCPN) and interhemispheric "callosal PN" (CPN)- during establishment of their distinct axonal connectivity. Using retrograde labeling of subtype-specific somata, purification by fluorescence-activated cell sorting, ribosome immunoprecipitation, and ultra-low-input mass spectrometry, we identify distinct protein compositions of RCs from these two subtypes. Strikingly, we identify 16 associated proteins reliably and exclusively detected only in RCs of SCPN. 11 of these proteins have known interaction with components of ribosomes; we further validated ribosome interaction with protein kinase C epsilon (PRKCE), a candidate with roles in synaptogenesis. PRKCE and a subset of SCPN-specific candidate ribosome-associated proteins also exhibit enriched gene expression by SCPN. Together, these results indicate that ribosomal complexes exheq]ibit subtype-specific protein composition in distinct subtypes of cortical projection neurons during development, and identify potential candidates for further investigation of function in translational regulation involved in subtype-specific circuit formation.

neuroscience↗

bioRxiv2024

Bcl11b orchestrates subcerebral projection neuron axon development via cell-autonomous, non-cell-autonomous, and subcellular mechanisms

Both cell-intrinsic competency and extracellular cues regulate axon projection, but mechanisms that coordinate these elements remain poorly understood. Subcerebral projection neurons (SCPN) extend their primary axons from cortex through subcortical structures, including the striatum, targeting the brainstem and spinal cord. We identify that the transcription factor Bcl11b/Ctip2 functions in multiple independent neuron populations to control SCPN axon development. Bcl11b expressed by SCPN is required cell-autonomously for axonal outgrowth and efficient entry into the internal capsule within the striatum, while Bcl11b expressed by medium spiny neurons (MSN) non-cell-autonomously regulates SCPN axon fasciculation within the internal capsule and subsequent pathfinding. Further, integrated investigation of Bcl11b-null SCPN with transcriptomic, immunocytochemical, and in vivo growth cone purification approaches identifies that Cdh13 is localized along axons and on growth cone surfaces of SCPN in vivo, and mediates Bcl11b regulation of SCPN axonal outgrowth. Together, these results demonstrate that Bcl11b controls multiple aspects of SCPN axon development by coordinating intrinsic SCPN cell autonomous subcellular mechanisms and extrinsic MSN non-cell-autonomous mechanisms.

neuroscience↗

bioRxiv2024

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors

Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo, or for optimally informative disease modeling and/or therapeutic screening in vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing proneural Neurog2 expression by progenitors. We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2, while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2-driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.

neuroscience↗

bioRxiv2024

Symmetry in levels of axon-axon homophilic adhesion establishes topography in the corpus callosum and development of connectivity between brain hemispheres

Specific and highly diverse connectivity between functionally specialized regions of the nervous system is controlled at multiple scales, from anatomically organized connectivity following macroscopic axon tracts to individual axon target-finding and synapse formation. Identifying mechanisms that enable entire subpopulations of related neurons to project their axons with regional specificity within stereotyped tracts to form appropriate long-range connectivity is key to understanding brain development, organization, and function. Here, we investigate how axons of the cerebral cortex form precise connections between the two cortical hemispheres via the corpus callosum. We identify topographic principles of the developing trans-hemispheric callosal tract that emerge through intrinsic guidance executed by growing axons in the corpus callosum within the first postnatal week in mice. Using micro-transplantation of regionally distinct neurons, subtype-specific growth cone purification, subcellular proteomics, and in utero gene manipulation, we investigate guidance mechanisms of transhemispheric axons. We find that adhesion molecule levels instruct tract topography and target field guidance. We propose a model in which transcallosal axons in the developing brain perform a "handshake" that is guided through co-fasciculation with symmetric contralateral axons, resulting in the stereotyped homotopic connectivity between the brains hemispheres.

neuroscience↗

bioRxiv2023

Dynamic subtype- and context-specific subcellular RNA regulation in growth cones of neocortical projection neurons

Molecular mechanisms that cells employ to compartmentalize function via localization of function-specific RNA and translation are only partially elucidated. We investigate long-range projection neurons of the cerebral cortex as highly polarized exemplars to elucidate dynamic regulation of RNA localization, stability, and translation within growth cones (GCs), leading tips of growing axons. Comparison of GC-localized transcriptomes between two distinct subtypes of projection neurons- interhemispheric-callosal and corticothalamic- across developmental stages identifies both distinct and shared subcellular machinery, and intriguingly highlights enrichment of genes associated with neurodevelopmental and neuropsychiatric disorders. Developmental context-specific components of GC-localized transcriptomes identify known and novel potential regulators of distinct phases of circuit formation: long-distance growth, target area innervation, and synapse formation. Further, we investigate mechanisms by which transcripts are enriched and dynamically regulated in GCs, and identify GC-enriched motifs in 3 untranslated regions. As one example, we identify cytoplasmic adenylation element binding protein 4 (CPEB4), an RNA binding protein regulating localization and translation of mRNAs encoding molecular machinery important for axonal branching and complexity. We also identify RNA binding motif single stranded interacting protein 1 (RBMS1) as a dynamically expressed regulator of RNA stabilization that enables successful callosal circuit formation. Subtly aberrant associative and integrative cortical circuitry can profoundly affect cortical function, often causing neurodevelopmental and neuropsychiatric disorders. Elucidation of context-specific subcellular RNA regulation for GC- and soma-localized molecular controls over precise circuit development, maintenance, and function offers generalizable insights for other polarized cells, and might contribute substantially to understanding neurodevelopmental and behavioral-cognitive disorders and toward targeted therapeutics.

neuroscience↗

bioRxiv2023

Limitations of fluorescent timer proteins toward isolation of developmentally and transcriptionally synchronized populations of human pluripotent stem cells and neural progenitors highlight unique expression and fluorescence maturation kinetics by human cells

Differentiation of human pluripotent stem cells (hPSC) into distinct neuronal populations holds substantial potential for disease modeling in vitro, toward both elucidation of pathobiological mechanisms and screening of potential therapeutic agents. For successful differentiation of hPSCs into subtype-specific neurons using in vitro protocols, detailed understanding of the transcriptional networks and their dynamic programs regulating endogenous cell fate decisions is critical. One major roadblock is the heterochronic nature of neurodevelopment, during which distinct cells and cell types in the brain and during in vitro differentiation mature and acquire their fates in an unsynchronized manner, hindering pooled transcriptional comparisons. One potential approach is to "translate" chronologic time into linear developmental and maturational time. Attempts to partially achieve this using simple binary promotor-driven fluorescent proteins (FPs) to pool similar cells have not been able to achieve this goal, due to asynchrony of promotor onset in individual cells. Toward solving this, we generated and tested a range of knock-in hPSC lines that express five distinct dual FP timer systems or single time-resolved fluorescent timer (FT) molecules, either in 293T cells or in human hPSCs driving expression from the endogenous paired box 6 (PAX6) promoter of cerebral cortex progenitors. While each of these dual FP or FT systems faithfully reported chronologic time when expressed from a strong inducible promoter in 293T cells, none of the tested FP/FT constructs followed the same fluorescence kinetics in developing human neural progenitor cells, and were unsuccessful in identification and isolation of distinct, developmentally synchronized cortical progenitor populations based on ratiometric fluorescence. This work highlights unique and often surprising expression kinetics and regulation in specific cell types differentiating from hPSCs.

neuroscience↗

bioRxiv2023

BEAM: a combinatorial recombinase toolbox for binary gene expression and mosaic analysis

Genetic mosaic analysis, in which mutant cells reside intermingled with wild-type cells, is a powerful experimental approach, but has not been widely used in mice because existing genome-based strategies require complicated and protracted breeding schemes. We have developed an alternative approach termed BEAM (for Binary Expression Aleatory Mosaic) that relies on sparse recombinase activation to generate two genetically distinct, non-overlapping populations of cells for comparative analysis. Following delivery of DNA constructs by transfection or viral transduction, combinatorial recombinase activity generates two distinct populations of cells labeled with either green or red fluorescent protein. Any gene of interest can be mis-expressed or deleted in one population for comparison with intermingled control cells. We have extensively optimized and characterized this system both in vitro and in vivo, and demonstrate its power for investigating cell autonomy, identifying temporally or spatially aberrant phenotypes, revealing changes in cell proliferation or death, and controlling for procedural variability.

genetics↗

bioRxiv2022

ASD gene Bcl11a regulates subcellular RNA localization, associative circuitry, and social behavior

Precise, area-specific connectivity of interhemispheric callosal projection neurons (CPN) in the cerebral cortex is critical for sensory, associative, and behavioral functions. CPN circuitry, which connects and integrates the cerebral hemispheres via the corpus callosum, is centrally implicated in autism spectrum disorder (ASD) and intellectual disability (ID). Though transcriptional controls regulating CPN subtype and areal development are partially understood, downstream subcellular molecular machinery that implements CPN circuitry is essentially unknown. Here, we identify that the highly penetrant ASD/ID risk gene Bcl11a/Ctip1 is critical developmentally for appropriate and precise areal targeting of superficial layer CPN (CPNSL) projections, and that its deletion strikingly re-routes some CPNSL projections subcortically, causes dramatic disruption to subcellular CPNSL growth cone (GC) molecular machinery, and disrupts social behavior and cognition in mice. CPNSL-specific embryonic deletion of Bcl11a causes loss of correct homotopic targeting in the contralateral cortex, re-routes a substantial proportion of axonal projections through the anterior commissure, and induces strikingly aberrant, but specific and precise, projections to the basolateral amygdala. Importantly, bilateral deletion of Bcl11a from CPNSL results in abnormal social behavior and working memory. Mechanistically, we identify dysregulation of the CPNSL axonal GC-localized transcriptome in Bcl11a nulls, due to either aberrant transcription or trafficking of individual transcripts. These molecular mis-localizations disrupt axon guidance and CPNSL circuitry formation. Together, this work identifies critical functions for Bcl11a in CPNSL axonal connectivity, development of functional associative-social circuitry, and regulation of subtype-specific subcellular molecular machinery in vivo, revealing novel GC-localized transcripts that regulate precise axonal targeting and circuit formation. These results elucidate development and ASD/ID disease-related circuit disruption of CPNSL, and the importance of understanding circuit-specific subcellular molecular machinery by neurons.

neuroscience↗

bioRxiv2022

Tle4 controls both developmental acquisition and postnatal maintenance of corticothalamic projection neuron identity

Identities, circuitry, and function of distinct neuron subtypes are specified during embryonic development, then maintained during postnatal maturation and potential plasticity. Mechanisms that control early acquisition of neuron subtype identities, encompassing circuitry and function, in the cerebral cortex have become increasingly understood. However, mechanisms controlling maintenance of identity, and accompanying regulation of plasticity, are largely unexplored and unknown. Here, we identify two novel functions of the co-repressor Tle4 in both acquisition and maintenance of neuron subtype identity of corticothalamic projection neurons. Embryonically, Tle4 promotes acquisition of corticothalamic molecular and cellular identity, and blocks emergence of core characteristics of subcerebral / corticospinal projection neuron identity, including morphology, gene expression, axonal connectivity, and circuitry. Postnatally, Tle4 is required to maintain corticothalamic molecular and projection identity during circuit maturation, avoiding potentially disruptive plasticity, but also limiting potentially beneficial plasticity. We identify an epigenetic mechanism by which TLE4 controls the activation state of loci regulating the level of Fezf2 expression by corticothalamic neurons during embryonic and postnatal development. This mechanism contributes importantly to distinction of cortical output (corticofugal) subtypes, and ensures appropriate maturation and maintenance of CThPN. HighlightsO_LITle4 promotes CThPN identity and blocks SCPN identity in early-born cortical neurons C_LIO_LITle4 is necessary to maintain CThPN identity during circuit maturation C_LIO_LITLE4-FEZF2 complex epigenetically regulates Fezf2 expression in developing CThPN C_LIO_LITLE4-FEZF2 regulates corticofugal subtypes distinction and maturation of CThPN C_LI

neuroscience↗

bioRxiv2022

Cbln1 directs axon targeting by corticospinal neurons specifically toward thoraco-lumbar spinal cord.

Corticospinal neurons (CSN) are centrally required for skilled voluntary movement, which necessitates that they establish precise subcerebral connectivity with the brainstem and spinal cord. However, molecular controls regulating specificity of this projection targeting remain largely unknown. We previously identified that developing CSN subpopulations exhibit striking axon targeting specificity in the spinal white matter. These CSN subpopulations with segmentally distinct spinal projections are also molecularly distinct; a subset of differentially expressed genes between these distinct CSN subpopulations function as molecular controls regulating differential axon projection targeting. Rostrolateral CSN extend axons exclusively to bulbar-cervical segments (CSNBC-lat), while caudomedial CSN (CSNmedial) are more heterogeneous, with distinct, intermingled subpopulations extending axons to either bulbar-cervical or thoraco-lumbar segments. Here, we report that Cerebellin 1 (Cbln1) is expressed specifically by CSN in medial, but not lateral, sensorimotor cortex. Cbln1 shows highly dynamic temporal expression, with Cbln1 levels in CSN highest during the period of peak axon extension toward thoraco-lumbar segments. Using gain-of-function experiments, we identify that Cbln1 is sufficient to direct thoraco-lumbar axon extension by CSN. Mis-expression of Cbln1 in CSNBC-lat either by in utero electroporation, or in postmitotic CSNBC-lat by AAV-mediated gene delivery, re-directs these axons past their normal bulbar-cervical targets toward thoracic segments. Further, Cbln1 overexpression in postmitotic CSNmedial increases the number of CSNmedial axons that extend past cervical segments into the thoracic cord. Collectively, these results identify that Cbln1 functions as a potent molecular control over thoraco-lumbar CSN axon extension, part of an integrated network of controls over segmentally-specific CSN axon projection targeting. Significance StatementCorticospinal neurons (CSN) exhibit remarkable diversity and precision of axonal projections to targets in the brainstem and distinct spinal segments; the molecular basis for this targeting diversity is largely unknown. CSN subpopulations projecting to distinct targets are also molecularly distinguishable. Distinct subpopulations degenerate in specific motor neuron diseases, further suggesting that intrinsic molecular differences might underlie differential vulnerability to disease. Here, we identify a novel molecular control, Cbln1, expressed by CSN extending axons to thoraco-lumbar spinal segments. Cbln1 is sufficient, but not required, for CSN axon extension toward distal spinal segments, and Cbln1 expression is controlled by recently identified, CSN-intrinsic regulators of axon extension. Our results identify that Cbln1, together with other regulators, coordinates segmentally precise CSN axon targeting.

neuroscience↗

bioRxiv2022

Development of ultra-low-input nanoRibo-seq enables quantification of translational control, revealing broad uORF translation by subtype-specific neurons

While increasingly powerful approaches enable investigation of transcription using small samples of RNA, approaches to investigate translational regulation in small populations of specific cell types, and/or (sub)-cellular contexts are lacking. Comprehensive investigation of mRNAs actively translated into proteins from ultra-low input material would provide important insight into molecular machinery and mechanisms underlying many cellular, developmental, and disease processes in vivo. Such investigations are limited by the large input required for current state-of-the-art Ribo-seq. Here, we present an optimized, ultra-low input "nanoRibo-seq" approach using 102 - 103-fold less input material than standard approaches, demonstrated here in subtype-specific neurons. nanoRibo-seq requires as few as 2.5K neurons, and exhibits rigorous quality control features: 1) strong enrichment for CDS versus UTRs and non-CDS; 2) narrow, distinct length distributions over CDS; 3) ribosome P-sites predominantly in-frame to annotated CDS; and 4) sufficient ribosome-protected fragment (RPF) coverage across thousands of mRNAs. As proof-of-concept, we calculate translation efficiencies from paired Ribo-seq and alkaline fragmented control libraries from "callosal projection neurons" (CPN), revealing divergence between mRNA abundance and RPF abundance for hundreds of genes. Intriguingly, we identify substantial translation of upstream ORFs in the 5 UTRs of genes involved in axon guidance and synapse assembly. nanoRibo-seq enables previously inaccessible investigation of translational regulation by small, specific cell populations in normal or perturbed contexts.

molecular biology↗

bioRxiv2021

Lumican regulates cervical corticospinal axon collateralization via non-autonomous crosstalk between distinct corticospinal neuron subpopulations

Corticospinal neurons (CSN) are the cortical projection neurons that innervate the spinal cord and some brainstem targets with segmental precision to control voluntary movement of specific functional motor groups, limb sections, or individual digits. CSN subpopulations exhibit striking axon targeting specificity from development into maturity: Evolutionarily newer rostrolateral CSN exclusively innervate bulbar-cervical targets (CSNBC-lat), while evolutionarily older caudomedial CSN (CSNmedial) are more heterogeneous, with distinct subpopulations extending axons to either bulbar-cervical or thoraco-lumbar segments. However, molecular regulation over specificity of CSN segmental target innervation is essentially unknown. The cervical cord, with its evolutionarily enhanced precision of forelimb movement, is innervated by multiple CSN subpopulations, suggesting inter-neuronal interactions in establishing cervical corticospinal circuitry. Here, we identify that Lumican, previously unrecognized in axon development, controls the balance of innervation between CSNBC-lat and CSNmedial within the cervical spinal cord. Remarkably, Lumican, an extracellular matrix protein expressed by CSNBC-lat, non-cell-autonomously suppresses axon collateralization in the cervical cord by CSNmedial. Intersectional viral labeling and mouse genetics further identify that Lumican controls axon collateralization by multiple CSN subpopulations in caudomedial sensorimotor cortex. These results identify inter-axonal molecular crosstalk between CSN subpopulations as a novel mechanism controlling corticospinal circuitry, target density, and competitive specificity. Further, this mechanism has potential implications for evolutionary diversification of corticospinal circuitry with finer scale precision.

neuroscience↗

bioRxiv2020

Fezf2 transient expression via modRNA with concurrent SIRT1 inhibition enhances differentiation of cortical subcerebral / corticospinal neuron identity from mES cells

During late embryonic development of the cerebral cortex, the major class of cortical output neurons termed subcerebral projection neurons (SCPN; including the predominant population of corticospinal neurons, CSN) and the class of interhemispheric callosal projection neurons (CPN) initially express overlapping molecular controls that later undergo subtype-specific refinements. Such molecular refinements are largely absent in heterogeneous, maturation-stalled, neocortical-like neurons (termed "cortical" here) spontaneously generated by established embryonic stem cell (ES) and induced pluripotent stem cell (iPSC) differentiation. Building on recently identified central molecular controls over SCPN development, we used a combination of synthetic modified mRNA (modRNA) for Fezf2, the central transcription factor controlling SCPN specification, and small molecule screening to investigate whether distinct chromatin modifiers might complement Fezf2 functions to promote SCPN-specific differentiation by mouse ES (mES)-derived cortical-like neurons. We find that the inhibition of a specific histone deacetylase, Sirtuin 1 (SIRT1), enhances refinement of SCPN subtype molecular identity by both mES-derived cortical-like neurons and primary dissociated E12.5 mouse cortical neurons. In vivo, we identify that SIRT1 is specifically expressed by CPN, but not SCPN, during late embryonic and postnatal differentiation. Together, these data indicate that SIRT1 has neuronal subtype-specific expression in the mouse cortex in vivo, and its inhibition enhances subtype-specific differentiation of highly clinically relevant SCPN / CSN cortical neurons in vitro.

neuroscience↗