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1.
Cell ; 174(3): 505-520, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30053424

RESUMO

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.


Assuntos
Mapeamento Cromossômico/métodos , Transtornos do Neurodesenvolvimento/genética , Biologia de Sistemas/métodos , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Humanos , Neurobiologia/métodos , Neuropsiquiatria
2.
Physiol Rev ; 2024 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-39480263

RESUMO

At the simplest level, neurons are structured to integrate synaptic input and perform computational transforms on that input, converting it into an action potential (AP) code. This process-converting synaptic input into AP output-typically occurs in a specialized region of axon termed the axon initial segment (AIS). The AIS, as its name implies, is often contained to the first section of axon abutted to the soma and is home to a dizzying array of ion channels, attendant scaffolding proteins, intracellular organelles, extracellular proteins, and, in some cases, synapses. The AIS serves multiple roles as the final arbiter for determining if inputs are sufficient to evoke APs, as a gatekeeper that physically separates the somatodendritic domain from the axon proper, and as a regulator of overall neuronal excitability, dynamically tuning its size to best suit the needs of parent neurons. These complex roles have received considerable attention from experimentalists and theoreticians alike. Here, we review recent advances in our understanding of the AIS and its role in neuronal integration and polarity in health and disease.

3.
J Neurosci ; 43(37): 6357-6368, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37596053

RESUMO

Neurons are remarkably polarized structures: dendrites spread and branch to receive synaptic inputs while a single axon extends and transmits action potentials (APs) to downstream targets. Neuronal polarity is maintained by the axon initial segment (AIS), a region between the soma and axon proper that is also the site of action potential (AP) generation. This polarization between dendrites and axons extends to inhibitory neurotransmission. In adulthood, the neurotransmitter GABA hyperpolarizes dendrites but instead depolarizes axons. These differences in function collide at the AIS. Multiple studies have shown that GABAergic signaling in this region can share properties of either the mature axon or mature dendrite, and that these properties evolve over a protracted period encompassing periadolescent development. Here, we explored how developmental changes in GABAergic signaling affect AP initiation. We show that GABA at the axon initial segment inhibits action potential initiation in layer (L)2/3 pyramidal neurons in prefrontal cortex from mice of either sex across GABA reversal potentials observed in periadolescence. These actions occur largely through current shunts generated by GABAA receptors and changes in voltage-gated channel properties that affected the number of channels that could be recruited for AP electrogenesis. These results suggest that GABAergic neurons targeting the axon initial segment provide an inhibitory "veto" across the range of GABA polarity observed in normal adolescent development, regardless of GABAergic synapse reversal potential.Significance Statement GABA receptors are a major class of neurotransmitter receptors in the brain. Typically, GABA receptors inhibit neurons by allowing influx of negatively charged chloride ions into the cell. However, there are cases where local chloride concentrations promote chloride efflux through GABA receptors. Such conditions exist early in development in neocortical pyramidal cell axon initial segments (AISs), where action potentials (APs) initiate. Here, we examined how chloride efflux in early development interacts with mechanisms that support action potential initiation. We find that this efflux, despite moving membrane potential closer to action potential threshold, is nevertheless inhibitory. Thus, GABA at the axon initial segment is likely to be inhibitory for action potential initiation independent of whether chloride flows out or into neurons via these receptors.


Assuntos
Segmento Inicial do Axônio , Animais , Camundongos , Potenciais de Ação , Cloretos , Neurônios GABAérgicos , Receptores de GABA-A , Ácido gama-Aminobutírico
4.
Hum Mol Genet ; 31(17): 2964-2988, 2022 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-35417922

RESUMO

Genetic variants in SCN2A, encoding the NaV1.2 voltage-gated sodium channel, are associated with a range of neurodevelopmental disorders with overlapping phenotypes. Some variants fit into a framework wherein gain-of-function missense variants that increase neuronal excitability lead to developmental and epileptic encephalopathy, while loss-of-function variants that reduce neuronal excitability lead to intellectual disability and/or autism spectrum disorder (ASD) with or without co-morbid seizures. One unique case less easily classified using this framework is the de novo missense variant SCN2A-p.K1422E, associated with infant-onset developmental delay, infantile spasms and features of ASD. Prior structure-function studies demonstrated that K1422E substitution alters ion selectivity of NaV1.2, conferring Ca2+ permeability, lowering overall conductance and conferring resistance to tetrodotoxin (TTX). Based on heterologous expression of K1422E, we developed a compartmental neuron model incorporating variant channels that predicted reductions in peak action potential (AP) speed. We generated Scn2aK1422E mice and characterized effects on neurons and neurological/neurobehavioral phenotypes. Cultured cortical neurons from heterozygous Scn2aK1422E/+ mice exhibited lower current density with a TTX-resistant component and reversal potential consistent with mixed ion permeation. Recordings from Scn2aK1442E/+ cortical slices demonstrated impaired AP initiation and larger Ca2+ transients at the axon initial segment during the rising phase of the AP, suggesting complex effects on channel function. Scn2aK1422E/+ mice exhibited rare spontaneous seizures, interictal electroencephalogram abnormalities, altered induced seizure thresholds, reduced anxiety-like behavior and alterations in olfactory-guided social behavior. Overall, Scn2aK1422E/+ mice present with phenotypes similar yet distinct from other Scn2a models, consistent with complex effects of K1422E on NaV1.2 channel function.


Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/genética , Cálcio/metabolismo , Humanos , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Permeabilidade , Convulsões/genética , Sódio/metabolismo , Canais de Sódio/genética
5.
J Neurosci ; 41(17): 3764-3776, 2021 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-33731449

RESUMO

The axon initial segment (AIS) is a specialized neuronal compartment in which synaptic input is converted into action potential (AP) output. This process is supported by a diverse complement of sodium, potassium, and calcium channels (CaV). Different classes of sodium and potassium channels are scaffolded at specific sites within the AIS, conferring unique functions, but how calcium channels are functionally distributed within the AIS is unclear. Here, we use conventional two-photon laser scanning and diffraction-limited, high-speed spot two-photon imaging to resolve AP-evoked calcium dynamics in the AIS with high spatiotemporal resolution. In mouse layer 5 prefrontal pyramidal neurons, calcium influx was mediated by a mix of CaV2 and CaV3 channels that differentially localized to discrete regions. CaV3 functionally localized to produce nanodomain hotspots of calcium influx that coupled to ryanodine-sensitive stores, whereas CaV2 localized to non-hotspot regions. Thus, different pools of CaVs appear to play distinct roles in AIS function.SIGNIFICANCE STATEMENT The axon initial segment (AIS) is the site where synaptic input is transformed into action potential (AP) output. It achieves this function through a diverse complement of sodium, potassium, and calcium channels (CaV). While the localization and function of sodium channels and potassium channels at the AIS is well described, less is known about the functional distribution of CaVs. We used high-speed two-photon imaging to understand activity-dependent calcium dynamics in the AIS of mouse neocortical pyramidal neurons. Surprisingly, we found that calcium influx occurred in two distinct domains: CaV3 generates hotspot regions of calcium influx coupled to calcium stores, whereas CaV2 channels underlie diffuse calcium influx between hotspots. Therefore, different CaV classes localize to distinct AIS subdomains, possibly regulating distinct cellular processes.


Assuntos
Segmento Inicial do Axônio/fisiologia , Segmento Inicial do Axônio/ultraestrutura , Canais de Cálcio/fisiologia , Sinalização do Cálcio/fisiologia , Potenciais de Ação/fisiologia , Animais , Axônios , Caveolina 2/efeitos dos fármacos , Caveolina 2/fisiologia , Caveolina 3/efeitos dos fármacos , Caveolina 3/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Confocal , Rianodina/farmacologia , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos
6.
Dev Neurosci ; 43(3-4): 201-221, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34139699

RESUMO

Neurodevelopmental disorders (NDDs) that affect cognition, social interaction, and learning, including autism spectrum disorder (ASD) and intellectual disability (ID), have a strong genetic component. Our current understanding of risk genes highlights two main groups of dysfunction: those in genes that act as chromatin modifiers and those in genes that encode for proteins localized at or near synapses. Understanding how dysfunction in these genes contributes to phenotypes observed in ASD and ID remains a major question in neuroscience. In this review, we highlight emerging evidence suggesting that dysfunction in dendrites - regions of neurons that receive synaptic input - may be key to understanding features of neuronal processing affected in these disorders. Dendritic integration plays a fundamental role in sensory processing, cognition, and conscious perception, processes hypothesized to be impaired in NDDs. Many high-confidence ASD genes function within dendrites where they control synaptic integration and dendritic excitability. Further, increasing evidence demonstrates that several ASD/ID genes, including chromatin modifiers and transcription factors, regulate the expression or scaffolding of dendritic ion channels, receptors, and synaptic proteins. Therefore, we discuss how dysfunction of subsets of NDD-associated genes in dendrites leads to defects in dendritic integration and excitability and may be one core phenotype in ASD and ID.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Transtorno do Espectro Autista/genética , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios , Sinapses
7.
Annu Rev Neurosci ; 35: 249-65, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22443507

RESUMO

The action potential generally begins in the axon initial segment (AIS), a principle confirmed by 60 years of research; however, the most recent advances have shown that a very rich biology underlies this simple observation. The AIS has a remarkably complex molecular composition, with a wide variety of ion channels and attendant mechanisms for channel localization, and may feature membrane domains each with distinct roles in excitation. Its function may be regulated in the short term through the action of neurotransmitters, in the long term through activity- and Ca(2+)-dependent processes. Thus, the AIS is not merely the beginning of the axon, but rather a key site in the control of neuronal excitability.


Assuntos
Potenciais de Ação/fisiologia , Axônios/fisiologia , Canais Iônicos/fisiologia , Transmissão Sináptica/fisiologia , Animais , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia
8.
J Neurosci ; 37(24): 5846-5860, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28522735

RESUMO

The D3 dopamine receptor, a member of the Gi-coupled D2 family of dopamine receptors, is expressed throughout limbic circuits affected in neuropsychiatric disorders, including prefrontal cortex (PFC). These receptors are important for prefrontal executive function because pharmacological and genetic manipulations that affect prefrontal D3 receptors alter anxiety, social interaction, and reversal learning. However, the mechanisms by which D3 receptors regulate prefrontal circuits and whether D3 receptors regulate specific prefrontal subnetworks remains unknown. Here, we combine dopamine receptor reporter lines, anatomical tracing techniques, and electrophysiology to show that D3 receptor expression defines a novel subclass of layer 5 glutamatergic pyramidal cell in mouse PFC (either sex). D3-receptor-expressing pyramidal neurons are electrophysiologically and anatomically separable from neighboring neurons expressing D1 or D2 receptors based on their dendritic morphology and subthreshold and suprathreshold intrinsic excitability. D3-receptor-expressing neurons send axonal projections to intratelencephalic (IT) targets, including contralateral cortex, nucleus accumbens, and basolateral amygdala. Within these neurons, D3 receptor activation was found to regulate low-voltage-activated CaV3.2 calcium channels localized to the axon initial segment, which suppressed action potential (AP) excitability, particularly when APs occurred at high frequency. Therefore, these data indicate that D3 receptors regulate the excitability of a unique, IT prefrontal cell population, thereby defining novel circuitry and cellular actions for D3 receptors in PFC.SIGNIFICANCE STATEMENT The D3 dopamine receptor, a member of the Gi-coupled D2 family of dopamine receptors, are expressed throughout limbic circuits, including prefrontal cortex (PFC). They are of broad interest as a site for therapeutic intervention in serious mental illness, yet we know very little about their distribution or function within PFC. Here, we show that D3 receptors define a unique population of glutamatergic principal cells in mouse PFC that largely lack expression of D1 or D2 receptors. Within these cells, we find that D3 receptors regulate the ability to generate high-frequency action potential bursts through mechanisms not supported by other dopamine receptors. These results define unique circuitry and cellular actions for D3 receptors in regulating PFC networks.


Assuntos
Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Receptores de Dopamina D3/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Feminino , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal/citologia , Células Piramidais/classificação , Células Piramidais/citologia
9.
J Neurosci ; 37(35): 8315-8329, 2017 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-28739583

RESUMO

Dopamine neurons in the ventral tegmental area (VTA) encode reward prediction errors and can drive reinforcement learning through their projections to striatum, but much less is known about their projections to prefrontal cortex (PFC). Here, we studied these projections and observed phasic VTA-PFC fiber photometry signals after the delivery of rewards. Next, we studied how optogenetic stimulation of these projections affects behavior using conditioned place preference and a task in which mice learn associations between cues and food rewards and then use those associations to make choices. Neither phasic nor tonic stimulation of dopaminergic VTA-PFC projections elicited place preference. Furthermore, substituting phasic VTA-PFC stimulation for food rewards was not sufficient to reinforce new cue-reward associations nor maintain previously learned ones. However, the same patterns of stimulation that failed to reinforce place preference or cue-reward associations were able to modify behavior in other ways. First, continuous tonic stimulation maintained previously learned cue-reward associations even after they ceased being valid. Second, delivering phasic stimulation either continuously or after choices not previously associated with reward induced mice to make choices that deviated from previously learned associations. In summary, despite the fact that dopaminergic VTA-PFC projections exhibit phasic increases in activity that are time locked to the delivery of rewards, phasic activation of these projections does not necessarily reinforce specific actions. Rather, dopaminergic VTA-PFC activity can control whether mice maintain or deviate from previously learned cue-reward associations.SIGNIFICANCE STATEMENT Dopaminergic inputs from ventral tegmental area (VTA) to striatum encode reward prediction errors and reinforce specific actions; however, it is currently unknown whether dopaminergic inputs to prefrontal cortex (PFC) play similar or distinct roles. Here, we used bulk Ca2+ imaging to show that unexpected rewards or reward-predicting cues elicit phasic increases in the activity of dopaminergic VTA-PFC fibers. However, in multiple behavioral paradigms, we failed to observe reinforcing effects after stimulation of these fibers. In these same experiments, we did find that tonic or phasic patterns of stimulation caused mice to maintain or deviate from previously learned cue-reward associations, respectively. Therefore, although they may exhibit similar patterns of activity, dopaminergic inputs to striatum and PFC can elicit divergent behavioral effects.


Assuntos
Aprendizagem por Associação/fisiologia , Comportamento de Escolha/fisiologia , Neurônios Dopaminérgicos/fisiologia , Estimulação Elétrica , Aprendizagem/fisiologia , Córtex Pré-Frontal/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Animal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/fisiologia , Recompensa
10.
Proc Natl Acad Sci U S A ; 111(35): 12919-24, 2014 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-25139992

RESUMO

To understand the cellular basis of learning and memory, the neurophysiology of the hippocampus has been largely examined in thin transverse slice preparations. However, the synaptic architecture along the longitudinal septo-temporal axis perpendicular to the transverse projections in CA1 is largely unknown, despite its potential significance for understanding the information processing carried out by the hippocampus. Here, using a battery of powerful techniques, including 3D digital holography and focal glutamate uncaging, voltage-sensitive dye, two-photon imaging, electrophysiology, and immunohistochemistry, we show that CA1 pyramidal neurons are connected to one another in an associational and well-organized fashion along the longitudinal axis of the hippocampus. Such CA1 longitudinal connections mediate reliable signal transfer among the pyramidal cells and express significant synaptic plasticity. These results illustrate a need to reconceptualize hippocampal CA1 network function to include not only processing in the transverse plane, but also operations made possible by the longitudinal network. Our data will thus provide an essential basis for future computational modeling studies on information processing operations carried out in the full 3D hippocampal network that underlies its complex cognitive functions.


Assuntos
Região CA1 Hipocampal/citologia , Região CA3 Hipocampal/citologia , Potenciação de Longa Duração/fisiologia , Memória de Curto Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Mapeamento Encefálico/métodos , Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Dendritos/fisiologia , Giro Denteado/citologia , Giro Denteado/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais , Células Piramidais/citologia , Células Piramidais/fisiologia , Ratos , Ratos Sprague-Dawley , Potenciais Sinápticos/fisiologia
11.
bioRxiv ; 2024 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-39149233

RESUMO

Opioids regulate circuits associated with motivation and reward across the brain. Of the opioid receptor types, delta opioid receptors (DORs) appear to have a unique role in regulating the activity of circuits related to reward without a liability for abuse. In neocortex, DORs are expressed primarily in interneurons, including parvalbumin- and somatostatin-expressing interneurons that inhibit somatic and dendritic compartments of excitatory pyramidal cells, respectively. But how DORs regulate transmission from these key interneuron classes is unclear. We found that DORs regulate inhibition from these interneuron classes using different G-protein signaling pathways that both converge on presynaptic calcium channels, but regulate distinct aspects of calcium channel function. This imposes different temporal filtering effects, via short-term plasticity, that depend on how calcium channels are regulated. Thus, DORs engage differential signaling cascades to regulate inhibition depending on the postsynaptic target compartment, with different effects on synaptic information transfer in somatic and dendritic domains.

12.
Neuron ; 112(9): 1444-1455.e5, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38412857

RESUMO

Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify a mechanism that underlies hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss of function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one's gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A-encoded NaV1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in mice via a CRISPR-activator approach that increases Scn2a expression, demonstrating that evaluation of a simple reflex can be used to assess and quantify successful therapeutic intervention.


Assuntos
Transtorno do Espectro Autista , Cerebelo , Canal de Sódio Disparado por Voltagem NAV1.2 , Plasticidade Neuronal , Animais , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.2/metabolismo , Camundongos , Plasticidade Neuronal/fisiologia , Cerebelo/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Humanos , Reflexo Vestíbulo-Ocular/fisiologia , Masculino , Células de Purkinje/metabolismo , Camundongos Endogâmicos C57BL
13.
Neuron ; 112(7): 1133-1149.e6, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38290518

RESUMO

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Neocórtex , Animais , Camundongos , Anquirinas/genética , Anquirinas/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Dendritos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Neocórtex/metabolismo , Células Piramidais/fisiologia
14.
Science ; 386(6721): eadi1025, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39480923

RESUMO

The innate immune system shapes brain development and is implicated in neurodevelopmental diseases. It is critical to define the relevant immune cells and signals and their impact on brain circuits. In this work, we found that group 2 innate lymphoid cells (ILC2s) and their cytokine interleukin-13 (IL-13) signaled directly to inhibitory interneurons to increase inhibitory synapse density in the developing mouse brain. ILC2s expanded and produced IL-13 in the developing brain meninges. Loss of ILC2s or IL-13 signaling to interneurons decreased inhibitory, but not excitatory, cortical synapses. Conversely, ILC2s and IL-13 were sufficient to increase inhibitory synapses. Loss of this signaling pathway led to selective impairments in social interaction. These data define a type 2 neuroimmune circuit in early life that shapes inhibitory synapse development and behavior.


Assuntos
Encéfalo , Imunidade Inata , Interleucina-13 , Interneurônios , Linfócitos , Meninges , Comportamento Social , Sinapses , Animais , Feminino , Camundongos , Encéfalo/imunologia , Encéfalo/crescimento & desenvolvimento , Interleucina-13/metabolismo , Interleucina-13/imunologia , Interneurônios/metabolismo , Interneurônios/fisiologia , Linfócitos/imunologia , Meninges/imunologia , Camundongos Endogâmicos C57BL , Transdução de Sinais , Sinapses/fisiologia , Transtornos do Neurodesenvolvimento/imunologia
15.
eNeuro ; 10(12)2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38151324

RESUMO

Dysfunction in the gene SCN2A, which encodes the voltage-gated sodium channel Nav1.2, is strongly associated with neurodevelopmental disorders including autism spectrum disorder and intellectual disability (ASD/ID). This dysfunction typically manifests in these disorders as a haploinsufficiency, where loss of one copy of a gene cannot be compensated for by the other allele. Scn2a haploinsufficiency affects a range of cells and circuits across the brain, including associative neocortical circuits that are important for cognitive flexibility and decision-making behaviors. Here, we tested whether Scn2a haploinsufficiency has any effect on a dynamic foraging task that engages such circuits. Scn2a +/- mice and wild-type (WT) littermates were trained on a choice behavior where the probability of reward between two options varied dynamically across trials and where the location of the high reward underwent uncued reversals. Despite impairments in Scn2a-related neuronal excitability, we found that both male and female Scn2a +/- mice performed these tasks as well as wild-type littermates, with no behavioral difference across genotypes in learning or performance parameters. Varying the number of trials between reversals or probabilities of receiving reward did not result in an observable behavioral difference, either. These data suggest that, despite heterozygous loss of Scn2a, mice can perform relatively complex foraging tasks that make use of higher-order neuronal circuits.


Assuntos
Haploinsuficiência , Canal de Sódio Disparado por Voltagem NAV1.2 , Animais , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Masculino , Feminino , Comportamento Animal , Aprendizagem , Recompensa , Tomada de Decisões , Humanos , Modelos Animais
16.
Biol Psychiatry ; 94(7): 531-542, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36931452

RESUMO

BACKGROUND: Second-generation antipsychotics (SGAs) are frontline treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the dopamine D3 receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling. METHODS: Here, we used a combination of two-photon calcium imaging, in vitro signaling assays, and mouse behavior to assess signaling by SGAs at D3R. RESULTS: We report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist SGA, but not an antagonist SGA, abolishes D3R function through postendocytic receptor degradation by GASP1 (G protein-coupled receptor-associated sorting protein-1). CONCLUSIONS: These results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that postendocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy.


Assuntos
Antipsicóticos , Dopamina , Camundongos , Animais , beta-Arrestina 2/metabolismo , Antipsicóticos/farmacologia , Receptores de Dopamina D3/metabolismo , Agonistas de Dopamina/farmacologia , Tolerância a Medicamentos , Receptores de Dopamina D1/metabolismo
17.
bioRxiv ; 2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-37333267

RESUMO

Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity, or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify the mechanisms that underlie hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss-of-function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one's gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A-encoded NaV1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in adolescent mice via a CRISPR-activator approach that increases Scn2a expression, highlighting how evaluation of simple reflexes can be used as quantitative readout of therapeutic interventions.

18.
J Neurosci ; 31(45): 16049-55, 2011 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-22072655

RESUMO

The axon initial segment (AIS) is a highly specialized neuronal subregion that is the site of action potential initiation and the boundary between axonal and somatodendritic compartments. In recent years, our understanding of the molecular structure of the AIS, its maturation, and its multiple fundamental roles in neuronal function has seen major advances. We are beginning to appreciate that the AIS is dynamically regulated, both over short timescales via adaptations in ion channel function, and long timescales via activity-dependent structural reorganization. Here, we review results from this emerging field highlighting how structural and functional plasticity relate to the development of the initial segment, and to neuronal disorders linked to AIS dysfunction.


Assuntos
Axônios/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Potenciais de Ação/fisiologia , Animais , Encéfalo/citologia , Humanos , Canais Iônicos/genética , Canais Iônicos/fisiologia , Modelos Biológicos , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Fatores de Tempo
19.
J Physiol ; 590(1): 109-18, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22063631

RESUMO

Spontaneously active neurons typically fire either in a regular pattern or in bursts. While much is known about the subcellular location and biophysical properties of conductances that underlie regular spontaneous activity, less is known about those that underlie bursts. Here, we show that T-type Ca(2+) channels localized to the site of action potential initiation in the axon initial segment play a pivotal role in spontaneous burst generation. In auditory brainstem interneurons, axon initial segment Ca(2+) influx is selectively downregulated by dopaminergic signalling. This regulation has marked effects on spontaneous activity, converting the predominant mode of spontaneous activity from bursts to regular spiking. Thus, the axon initial segment is a key site, and dopamine a key regulator, of spontaneous bursting activity.


Assuntos
Axônios/fisiologia , Canais de Cálcio Tipo T/fisiologia , Interneurônios/fisiologia , Potenciais de Ação/fisiologia , Animais , Cálcio/metabolismo , Dopamina/metabolismo , Regulação para Baixo , Potenciais Evocados Auditivos do Tronco Encefálico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA
20.
J Neurodev Disord ; 14(1): 11, 2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-35123407

RESUMO

BACKGROUND: Tbr1 encodes a T-box transcription factor and is considered a high confidence autism spectrum disorder (ASD) gene. Tbr1 is expressed in the postmitotic excitatory neurons of the deep neocortical layers 5 and 6. Postnatally and neonatally, Tbr1 conditional mutants (CKOs) have immature dendritic spines and reduced synaptic density. However, an understanding of Tbr1's function in the adult mouse brain remains elusive. METHODS: We used conditional mutagenesis to interrogate Tbr1's function in cortical layers 5 and 6 of the adult mouse cortex. RESULTS: Adult Tbr1 CKO mutants have dendritic spine and synaptic deficits as well as reduced frequency of mEPSCs and mIPSCs. LiCl, a WNT signaling agonist, robustly rescues the dendritic spine maturation, synaptic defects, and excitatory and inhibitory synaptic transmission deficits. CONCLUSIONS: LiCl treatment could be used as a therapeutic approach for some cases of ASD with deficits in synaptic transmission.


Assuntos
Transtorno do Espectro Autista , Animais , Transtorno do Espectro Autista/genética , Humanos , Camundongos , Neurogênese/fisiologia , Neurônios , Transmissão Sináptica , Proteínas com Domínio T/genética , Fatores de Transcrição
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