Biology subjects

Penzes, P.

Publications and source records attributed to Penzes, P..

16 recordsLinked to original sources

bioRxiv2025

Impairment of homeostatic structural plasticity caused by the autism and schizophrenia-associated 16p11.2 duplication

Homeostatic plasticity is essential for information processing and the stability of neuronal circuits, however its relevance to neuropsychiatric disorders remains unclear. The 16p11.2 duplication (BP4-BP5) is a genetic risk factor that strongly predisposes to a range of severe mental illnesses including autism, schizophrenia, intellectual disability, and epilepsy. The duplication consists of a 600 kb region on chromosome 16, including 27 protein-coding genes, with poorly defined effects on neuronal structure and function. Here, we used a mouse model of the 16p11.2 duplication to investigate the impact of this variant on synaptic structure and downstream homeostatic plasticity. We find that 16p11.2 duplication neurons exhibit overly branched dendritic arbors and excessive spine numbers, which host an overabundance of surface AMPA receptor subunit GluA1. Using a homeostatic plasticity paradigm, we show that 16p11.2 duplication neurons fail to undergo synaptic upscaling upon activity deprivation, consistent with disrupted structural plasticity. We also observe that the increased surface abundance of GluA1 occludes further insertion events, a critical mechanism for synaptic plasticity. Finally, we show that genetically correcting the dosage of 16p11.2-encoded Prrt2 to wild-type levels rescues structural spine phenotypes. Our work suggests that aberrant plasticity could contribute to the etiology of neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Pro-cognitive reshaping of neuronal dynamics by a human CSF-based factor

Neuronal connection dysfunction is a convergent cause of cognitive deficits in mental disorders. Cognitive processes are finely regulated at the synaptic level by membrane proteins, some of which are shed and detectable in patients cerebrospinal fluid (CSF). However, whether these soluble synaptic proteins can harnessed as innovative pro-cognitive factors to treat brain disorders remains unclear. Here, we use quantitative proteomics to identify shed synaptic proteins dysregulated in the CSF of subjects with schizophrenia (SCZ), a mental disorder characterized by cognitive and synaptic dysfunction. The level of a yet uncharacterized soluble form of the voltage-gated calcium channel auxiliary subunit, 2{delta}-1, is robustly reduced in SCZ CSF. Remarkably, soluble 2{delta}-1 is convergently downregulated across several brain disorder CSF proteomes. We show that the brain releases soluble 2{delta}-1 in an activity-dependent manner, which can reorganize neuronal network dynamics by binding to synaptic targets and promoting inhibitory neuron plasticity. A single brain injection of a synthetic soluble 2{delta}-1 improved interneuron and cognitive deficits in a mutant mouse model of SCZ and cortical dysfunction. These findings underscore the potential of shed synaptic proteins as novel therapeutic agents capable of enhancing brain function in diverse brain disorders characterized by cognitive impairment.

neuroscience↗

bioRxiv2024

ASD-ASSOCIATED CNTNAP2 VARIANTS DISRUPT NEURONAL ARBORIZATION THROUGH IMPAIRED REGULATION BY ECTODOMAIN SHEDDING

Ectodomain shedding (ES) is a process by which a protease cleaves the extracellular portion of membrane-bound proteins, releasing soluble fragments that influence diverse cellular functions. ES is critical in neurodevelopment, plasticity, and neurodegenerative disorders, such as Alzheimers disease, and has recently been implicated in neurodevelopmental conditions, including autism spectrum disorders (ASD). Contactin-associated protein-like 2 (CNTNAP2) is an adhesion molecule regulated by ES, releasing a soluble ectodomain (sCNTNAP2) that enhances neuronal synchrony. CNTNAP2 is implicated in ASD, schizophrenia, and cortical dysplasia focal epilepsy syndrome (CDFE) and it is known to regulate neuronal arborization, as well as dendritic spine maturation and maintenance. However, little is known about how neuroplasticity impacts ES or the role of CNTNAP2 ES in dendritic arborization. Here, we show that the brain sheddome is enriched in shed ectodomains that regulate neuronal projections, and that its molecular and functional composition is modulated by sensory deprivation in a sex dependent manner, with a decrease in sCNTNAP2 levels observed only in male mice. Furthermore, we demonstrate that sCNTNAP2 promotes dendritic arborization, while ASD-associated CNTNAP2 variants present reduced sCNTNAP2 levels in culture and decreased neuronal branching. Together, these findings underscore the role of ES in neuroplasticity and ASD and reveal how CNTNAP2 genetic variations disrupt its regulation by ES, leading to altered dendritic branching.

neuroscience↗

bioRxiv2022

Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub

Neuropsychiatric disorders (NPDs) share genetic etiology and are frequently co-morbid with epilepsy, but the biological basis of this shared risk remains poorly understood. The 16p11.2 microduplication (16p11.2dup/+) is a highly pleiotropic copy number variant (CNV) conferring risk for multiple NPDs including autism spectrum disorder, schizophrenia and intellectual disability, and is associated with a high prevalence of seizures. We used a mouse model of the 16p11.2 duplication (16p11.2dup/+) to uncover molecular and circuit properties associated with this broad phenotypic spectrum, and examined genes within the locus capable of phenotype reversal. Quantitative proteomics of cortical membranes revealed alterations to synaptic protein networks and products of diverse NPD risk genes in 16p11.2dup/+ mice. Network analysis identified an epilepsy-associated protein subnetwork, which was dysregulated in 16p11.2dup/+ mice and proteomic datasets from human NPDs. We investigated circuit properties in 16p11.2dup/+ mice and found they exhibited hypersynchronous activity and enhanced network glutamate release, which increased susceptibility to seizures. We hypothesized that a regulator of the synaptic and epilepsy-associated protein network could have an important impact on pathophysiology. Human brain co-expression and interactome analysis revealed PRRT2 as a major hub in the dysregulated epilepsy subnetwork. Remarkably, restoring Prrt2 copy number to wild-type levels rescued aberrant circuit properties, seizure susceptibility and social interaction deficits in 16p11.2dup/+ mice. We show that proteomics and network biology can identify important disease hubs in multigenic CNVs, and reveal molecular and circuit phenotypes which may be relevant to the complex symptomatology of 16p11.2 duplication carriers.

neuroscience↗

bioRxiv2022

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Copy number variations (CNV) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase (DUB) function. The OTUD7A protein-protein interaction (PPI) network revealed interactions with synaptic, axonal, and cytoskeletal proteins and was enriched for known ASD and epilepsy risk genes. The interactions between OTUD7A and the NDD risk genes Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment (AIS), while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Further, our study highlights the utility of targeting CNV genes using cell-type specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

neuroscience↗

bioRxiv2021

Multiple genes in cis mediate the effects of a single chromatin accessibility variant on aberrant synaptic development and function in human neurons

Despite hundreds of risk loci from genome-wide association studies of neuropsychiatric disorders, causal variants/genes remain largely unknown. Here, in NEUROG2-induced human neurons, we identified 31 risk SNPs in 26 schizophrenia (SZ) risk loci that displayed allele-specific open chromatin (ASoC) and were likely to be functional. Editing the strongest ASoC SNP rs2027349 near vacuolar protein sorting 45 homolog (VPS45) altered the expression of VPS45, lncRNA AC244033.2, and a distal gene, C1orf54, in human neurons. Notably, the global gene expression changes in neurons were enriched for SZ risk and correlated with post-mortem brain gene expression signatures of neuropsychiatric disorders. Neurons carrying the risk allele exhibited increased dendritic complexity, synaptic puncta density, and hyperactivity, which were reversed by knocking-down distinct cis-regulated genes (VPS45, AC244033.2, or C1orf54), suggesting a phenotypic contribution from all three genes. Interestingly, transcriptomic analysis of knockdown cells suggested a non-additive effects of these genes. Our study reveals a compound effect of multiple genes at a single SZ locus on synaptic development and function, providing a mechanistic link between a non-coding SZ risk variant and disease-related cellular phenotypes.

genetics↗

bioRxiv2021

A Kalirin Missense Mutation Enhances Dendritic RhoA Signaling and Leads to Regression of Cortical Dendritic Arbors Across Development

Normally, dendritic size is established prior to adolescence then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor, Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wildtype KAL. In mice containing this missense mutation at the endogenous locus there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Tissue density of dendritic spines was also reduced. Early adult mice with these structural deficts exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease. SIGNIFICANCE STATEMENTDendrites are long branching processes on neurons that contain small processes called spines that are the site of connections with other neurons, establishing cortical circuitry. Dendrites have long been considered stable structures, with rapid growth prior to adolescence followed by maintenance of size into adulthood. However, schizophrenia is characterized by accelerated reductions of cortical gray matter volume and onset of clinical symptoms during adolescence, with reductions in dendritic length present when examined after death. We show that dendrites retain the capacity for regression, and that a mild genetic vulnerability in a regression pathway leads to onset of structural impairments in previously formed dendrites across adolescence. This suggests that targeting specific regression pathways could potentially lead to new therapeutics for schizophrenia.

neuroscience↗

bioRxiv2019

Ankyrin-G-190 palmitoylation mediates dendrite and spine morphogenesis and is altered in response to lithium

AnkG, encoded by the ANK3 gene, is a multifunctional scaffold protein with complex isoform expression: the 480 kDa and 270 kDa isoforms have roles at the axon initial segment and node of Ranvier, whereas the 190 kDa isoform (AnkG-190) has an emerging role in the dendritic shaft and spine heads. All isoforms of AnkG undergo palmitoylation, a post-translational modification regulating protein attachment to lipid membranes. However, palmitoylation of AnkG-190 has not been investigated in dendritic spines. The ANK3 gene and altered expression of AnkG proteins are associated with a variety of neuropsychiatric and neurodevelopmental disorders including bipolar disorders and are implicated in the lithium response, a commonly used mood stabilizer for bipolar disorder patients, although the precise mechanisms involved are unknown. Here, we showed that Cys70 palmitoylation stabilizes the localization of AnkG-190 in spine heads and at dendritic plasma membrane nanodomains. Mutation of Cys70 impairs AnkG-190 function in dendritic spines and alters PSD-95 scaffolding. Interestingly, we find that lithium reduces AnkG-190 palmitoylation thereby increasing its mobility in dendritic spines. Finally, we demonstrate that the palmitoyl acyl transferase ZDHHC8, but not ZDHHC5, increases AnkG-190 stability in spine heads and is inhibited by lithium. Together, our data reveal that palmitoylation is critical for AnkG-190 localization and function and a potential ZDDHC8/AnkG-190 mechanism linking AnkG-190 mobility to the neuronal effects of lithium.

neuroscience↗

bioRxiv2019

Rapid 3D enhanced resolution microscopy reveals the dynamics of cortical dendritic spinules

Dendritic spinules are thin, membranous protrusions formed by neuronal dendritic spines that are not adequately resolved by diffraction-limited light microscopy. Hence, our understanding of spinules is inferred predominantly from fixed-tissue electron microscopy (EM). Super-resolution modalities have enabled live-cell nanoscopic imaging, but their utility for fast, time-lapse, volumetric imaging has been restricted. Herein, we utilized rapid structured illumination microscopy (SIM) and enhanced resolution confocal microscopy to study spatiotemporal spinule dynamics in live cultured cortical pyramidal neurons. Spinules on mushroom spines typically recurred at the same topographical locations and most were short-lived, originating near simple post-synaptic densities (PSDs), while a subset was long-lived and elongated, emerging from complex PSDs. Ca2+ puncta within spinules synchronized with spine head transients and Ca2+ depletion drastically decreased spinule number. Moreover, we uncovered evidence of differential Ca2+-mediated regulation of short-lived and long-lived spinules. Thus, we identified unique spinule classes divergent in lifespan, dynamics, morphology, relationship to the PSD, and regulation. These data suggest distinct synaptic functions of spinule classes, informing future studies, while demonstrating a new application for enhanced resolution microscopy.

neuroscience↗

bioRxiv2019

EPAC2 is required for corticotropin-releasing hormone-mediated spine loss

Corticotropin-releasing hormone (CRH) is produced in response to stress. This hormone plays a key role in mediating neuroendocrine, behavioral, and autonomic responses to stress. The CRH receptor 1 (CRHR1) is expressed in multiple brain regions including the cortex and hippocampus. Previous studies have shown that activation of CRHR1 by CRH results in the rapid loss of dendritic spines. Exchange protein directly activated by cAMP (EPAC2, also known as RapGEF4), a guanine nucleotide exchange factor (GEF) for the small GTPase Rap, has been linked with CRHR1 signaling. EPAC2 plays a critical role in regulating dendritic spine morphology and number in response to several extracellular signals. But whether EPAC2 links CRHR1 with dendritic spine remodeling is unknown. Here we show that CRHR1 is highly enriched in the dendritic spines of primary cortical neurons. Furthermore, we find that EPAC2 and CRHR1 co-localize in cortical neurons. Critically, short hairpin RNA-mediated knockdown of Epac2 abolished CRH-mediated spine loss in primary cortical neurons. Taken together, our data indicate that EPAC2 is required for the rapid loss of dendritic spines induced by CRH. These findings identify a novel pathway by which acute exposure to CRH may regulate synaptic structure and ultimately responses to acute stress.

neuroscience↗

bioRxiv2019

CNTNAP2 ectodomain, detected in neuronal and CSF sheddomes, modulates Ca2+ dynamics and network synchrony

SUMMARYWhile many neuronal membrane-anchored proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding. Using mass spectrometry (MS)-based proteomics, we showed that the neuronal sheddome mirrors human cerebrospinal fluid (hCSF). Among shed synaptic proteins in hCSF was the ectodomain of CNTNAP2 (CNTNAP2-ecto), a risk factor for neurodevelopmental disorders (NDD). Using structured-illumination microscopy (SIM), we mapped the spatial organization of neuronal CNTNAP2-ecto shedding. Using affinity chromatography followed by MS, we identified the ATP2B/PMCA Ca2+ extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto coimmunoprecipitates with PMCA2, a known autism risk factor, and enhances its activity, thereby modulating neuronal Ca2+ levels. Finally, we showed that CNTNAP2-ecto regulates neuronal network synchrony in primary cultures and brain slices. These data provide new insights into the biology of synaptic ectodomain shedding and reveal a novel mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony.

neuroscience↗

bioRxiv2019

CNTNAP2 is targeted to endosomes by the polarity protein Par3

A decade of genetic studies has established Contactin-associated protein-like 2 (CNTNAP2) as a prominent susceptibility gene associated with multiple neurodevelopmental disorders. The development and characterization of Cntnap2 knockout models in multiple species have bolstered this claim by establishing clear connections with certain endophenotypes. Despite these remarkable in vivo findings, CNTNAP2s molecular functions are relatively unexplored, highlighting the need to identify novel protein partners. Here, we characterized an interaction between CNTNAP2 and Partitioning-defective 3 (Par3) - a polarity molecule we isolated in a yeast-two hybrid screen with CNTNAP2s C-terminus. We provide evidence that the two proteins interact via PDZ domain-mediated binding, that CNTNAP2+/Par3+ complexes are largely associated with clathrin-coated endocytic vesicles, and that Par3 causes an enlargement of these structures. Live imaging and fluorescence recovery after photobleaching (FRAP) reveals that Par3 limits the mobility of CNTNAP2 at endosomes, thus stabilizing it at that location. Finally, expression of Par3 but not Par3{Delta}PDZ can cluster endogenous CNTNAP2 in primary neurons. Collectively, we conclude that Par3 regulates CNTNAP2 spatial localization to endocytic compartments.

neuroscience↗

bioRxiv2019

Impaired M-current in KCNQ2 Encephalopathy Evokes Dyshomeostatic Modulation of Excitability

Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells and gene editing to establish a disease model, and measured the functional properties of patient-derived neurons using electrophysiological and optical approaches. We find that while patient-derived excitatory neurons exhibit reduced M-current early, they develop intrinsic and network hyperexcitability progressively. This hyperexcitability is associated with faster action potential repolarization, larger afterhyperpolarization, and a functional enhancement of large conductance Ca2+-activated K+ (BK) channels. These properties facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Importantly, we were able to phenocopy these excitability features in control neurons only by chronic but not acute pharmacological inhibition of M-current. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function and lead to alterations in the neurodevelopmental trajectory of patient-derived neurons. Our work has therapeutic implications in explaining why KCNQ2 agonists are not beneficial unless started at an early disease stage.

neuroscience↗

bioRxiv2019

Loss of EPAC2 results in altered synaptic composition of dendritic spines and excitatory and inhibitory balance

EPAC2 is a guanine nucleotide exchange factor that regulates GTPase activity of the small GTPase Rap and Ras) and is highly enriched at synapses. Activation of EPAC2 has been shown to induce dendritic spine shrinkage and increase spine motility, effects that are necessary for synaptic plasticity. These morphological effects are dysregulated by rare mutations of EPAC2 associated with autism spectrum disorders. In addition, EPAC2 destabilizes synapses through the removal of synaptic GluA2/3-containing AMPA receptors. Previous work has shown that Epac2 knockout mice (Epac2-/-) display abnormal social interactions, as well as gross disorganization of the frontal cortex and abnormal spine motility in vivo. In this study we sought to further understand the cellular consequences of knocking out Epac2 on the development of neuronal and synaptic structure and organization of cortical neurons. Using primary cortical neurons generated from Epac2+/+ or Epac2-/- mice, we confirm that EPAC2 is required for cAMP-dependent spine shrinkage. Neurons from Epac2-/- mice also displayed increased synaptic expression of GluA2/3-containing AMPA receptors, as well as of the adhesion protein N-cadherin. Intriguingly, analysis of excitatory and inhibitory synaptic proteins revealed that loss of EPAC2 resulted in altered of expression of vesicular glutamate transporter 1 (VGluT1) and vesicular GABA transporter (VGAT), indicating a potential imbalance in excitatory/inhibitory inputs onto neurons. Finally, examination of cortical neurons located within the anterior cingulate cortex further revealed subtle deficits in the establishment of dendritic arborization in vivo. These data provide evidence that EPAC2 is required for the correct composition of synapses and that loss of this protein could result in an imbalance of excitatory and inhibitory synapses.

neuroscience↗

bioRxiv2018

Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders

Loss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17{beta}-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17{beta}-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17{beta}-estradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17{beta}-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17{beta}-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17{beta}-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon. Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number.

neuroscience↗

bioRxiv2018

Disruption of The Psychiatric Risk Gene Ankyrin 3 Enhances Microtubule Dynamics Through GSK3/CRMP2 Signaling

The ankyrin 3 gene (ANK3) is a well-established risk gene for psychiatric illness, but the mechanisms underlying its pathophysiology remain elusive. We examined the molecular effects of disrupting brain-specific Ank3 isoforms in mouse and neuronal model systems. RNA sequencing of hippocampus from Ank3+/- and Ank3+/+ mice identified altered expression of 282 genes that were enriched for microtubule-related functions. Results were supported by increased expression of microtubule end-binding protein 3 (EB3), an indicator of microtubule dynamics, in Ank3+/- mouse hippocampus. Live-cell imaging of EB3 movement in primary neurons from Ank3+/- mice revealed impaired elongation of microtubules. Using a CRISPR-dCas9-KRAB transcriptional repressor in mouse neuro-2a cells, we determined that repression of brain-specific Ank3 increased EB3 expression, decreased tubulin acetylation, and increased the soluble:polymerized tubulin ratio, indicating enhanced microtubule dynamics. These changes were rescued by inhibition of glycogen synthase kinase 3 (GSK3) with lithium or CHIR99021, a highly selective GSK3 inhibitor. Brain-specific Ank3 repression in neuro-2a cells increased GSK3 activity (reduced inhibitory phosphorylation) and elevated collapsin response mediator protein 2 (CRMP2) phosphorylation, a known GSK3 substrate and microtubule-binding protein. Pharmacological inhibition of CRMP2 activity attenuated the rescue of EB3 expression and tubulin polymerization in Ank3 repressed cells by lithium or CHIR99021, suggesting microtubule instability induced by Ank3 repression is dependent on CRMP2 activity. Taken together, our data indicate that aNK3 functions in neuronal microtubule dynamics through GSK3 and its downstream substrate CRMP2. These findings reveal cellular and molecular mechanisms underlying brain-specific ANK3 disruption that may be related to its role in psychiatric illness.

neuroscience↗