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Journal of Neuroscience
Journal Prestige (SJR): 4.466
Citation Impact (citeScore): 6
Number of Followers: 330  
  Full-text available via subscription Subscription journal
ISSN (Print) 0270-6474 - ISSN (Online) 1529-2401
Published by Society for Neuroscience Homepage  [2 journals]
  • This Week in The Journal
    • Pages: 6099 - 6099
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.twij.40.32.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Exploring the Therapeutic Potential of Protein Tyrosine Phosphatase 1B in
           hAPP-J20 Mouse Model of Alzheimer's Disease
    • Authors: Ghalayini; J.
      Pages: 6100 - 6102
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0852-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • N-Wasp Regulates Oligodendrocyte Myelination
    • Authors: Katanov, C; Novak, N, Vainshtein, A, Golani, O, Dupree, J. L, Peles, E.
      Pages: 6103 - 6111
      Abstract: Oligodendrocyte myelination depends on actin cytoskeleton rearrangement. Neural Wiskott-Aldrich syndrome protein(N-Wasp) is an actin nucleation factor that promotes polymerization of branched actin filaments. N-Wasp activity is essential for myelin membrane wrapping by Schwann cells, but its role in oligodendrocytes and CNS myelination remains unknown. Here we report that oligodendrocytes-specific deletion of N-Wasp in mice of both sexes resulted in hypomyelination (i.e., reduced number of myelinated axons and thinner myelin profiles), as well as substantial focal hypermyelination reflected by the formation of remarkably long myelin outfolds. These myelin outfolds surrounded unmyelinated axons, neuronal cell bodies, and other myelin profiles. The latter configuration resulted in pseudo-multimyelin profiles that were often associated with axonal detachment and degeneration throughout the CNS, including in the optic nerve, corpus callosum, and the spinal cord. Furthermore, developmental analysis revealed that myelin abnormalities were already observed during the onset of myelination, suggesting that they are formed by aberrant and misguided elongation of the oligodendrocyte inner lip membrane. Our results demonstrate that N-Wasp is required for the formation of normal myelin in the CNS. They also reveal that N-Wasp plays a distinct role in oligodendrocytes compared with Schwann cells, highlighting a difference in the regulation of actin dynamics during CNS and PNS myelination.SIGNIFICANCE STATEMENT Myelin is critical for the normal function of the nervous system by facilitating fast conduction of action potentials. During the process of myelination in the CNS, oligodendrocytes undergo extensive morphological changes that involve cellular process extension and retraction, axonal ensheathment, and myelin membrane wrapping. Here we present evidence that N-Wasp, a protein regulating actin filament assembly through Arp2/3 complex-dependent actin nucleation, plays a critical role in CNS myelination, and its absence leads to several myelin abnormalities. Our data provide an important step into the understanding of the molecular mechanisms underlying CNS myelination.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0912-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Activity and Cytosolic Na+ Regulate Synaptic Vesicle Endocytosis
    • Authors: Zhu, Y; Li, D, Huang, H.
      Pages: 6112 - 6120
      Abstract: Retrieval of synaptic vesicles via endocytosis is essential for maintaining sustained synaptic transmission, especially for neurons that fire action potentials at high frequencies. However, how neuronal activity regulates synaptic vesicle recycling is largely unknown. Here we report that Na+ substantially accumulated in the mouse calyx of Held terminals of either sex during repetitive high-frequency spiking. Elevated presynaptic Na+ accelerated both slow and rapid forms of endocytosis and facilitated endocytosis overshoot, but did not affect the readily releasable pool size, Ca2+ influx, or exocytosis. To examine whether this facilitation of endocytosis is related to the Na+-dependent vesicular content change, we dialyzed glutamate into the presynaptic cytosol or blocked the vesicular glutamate uptake with bafilomycin and found that the rate of endocytosis was not affected by regulating the vesicular glutamate content. Endocytosis is critically dependent on intracellular Ca2+, and the activity of Na+/Ca2+ exchanger (NCX) may be altered when the Na+ gradient is changed. However, neither NCX inhibitor nor change of extracellular Na+ concentration affected the endocytosis rate. Moreover, two-photon Ca2+ imaging showed that presynaptic Na+ did not affect the action potential-evoked intracellular Ca2+ transient and decay. Therefore, we revealed a novel mechanism of cytosolic Na+ in accelerating vesicle endocytosis. During high-frequency synaptic transmission, when large numbers of synaptic vesicles were fused, the rapid buildup of presynaptic cytosolic Na+ promoted vesicle recycling and sustained synaptic transmission.SIGNIFICANCE STATEMENT High-frequency firing neurons are widely distributed in the CNS. A large number of synaptic vesicles are released during high-frequency synaptic transmission; accordingly, synaptic vesicles need to be recycled rapidly to replenish the vesicle pool. Synaptic vesicle exocytosis and endocytosis are tightly coupled, and their coupling is essential for synaptic function and structural stability. We showed here that intracellular Na+ concentration at the calyx of Held terminal increased rapidly during spike activity and the increased Na+ accelerated endocytosis. Thus, when large numbers of synaptic vesicles are released during high-frequency synaptic transmission, Na+ accumulated in terminals and facilitated vesicle recycling. These findings represent a novel cellular mechanism that supports reliable synaptic transmission at high frequency in the CNS.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0119-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Deletion of the Mitochondrial Matrix Protein CyclophilinD Prevents
           Parvalbumin Interneuron Dysfunctionand Cognitive Deficits in a Mouse Model
           of NMDA Hypofunction
    • Authors: Phensy, A; Lindquist, K. L, Lindquist, K. A, Bairuty, D, Gauba, E, Guo, L, Tian, J, Du, H, Kroener, S.
      Pages: 6121 - 6132
      Abstract: Redox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin (PV)-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory and cognitive processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors (NMDARs) during development [subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11] results in long-lasting alterations in synaptic transmission and reduced PV expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif–/–) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition (NOR). Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes.SIGNIFICANCE STATEMENT Mitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor (NMDAR) blockade with ketamine (KET) during development causes oxidative stress, dysfunction of parvalbumin (PV)-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D (CypD) show robust protection from PVI dysfunction following perinatal NMDAR blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0880-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Developmentally Transient CB1Rs on Cerebellar Afferents Suppress Afferent
    • Authors: Barnes, J. L; Mohr, C, Ritchey, C. R, Erikson, C. M, Shiina, H, Rossi, D. J.
      Pages: 6133 - 6145
      Abstract: The endocannabinoid system plays important roles in brain development, but mechanistic studies have focused on neuronal differentiation, migration, and synaptogenesis, with less attention to transcellular interactions that coordinate neurodevelopmental processes across developing neural networks. We determined that, in the developing rodent cerebellar cortex (of both sexes), there is a transient window when the dominant brain cannabinoid receptor, CB1R, is expressed on afferent terminals instead of output neuron Purkinje cell synapses that dominate the adult cerebellum. Activation of these afferent CB1Rs suppresses synaptic transmission onto developing granule cells, and consequently also suppresses excitation of downstream neurons in the developing cortical network, including nonsynaptic, migrating neurons. Application of a CB1R antagonist during afferent stimulation trains and depolarizing voltage steps caused a significant, sustained potentiation of synaptic amplitude. Our data demonstrate that transiently expressed afferent CB1Rs regulate afferent synaptic strength during synaptogenesis, which enables coordinated dampening of transcortical developmental signals.SIGNIFICANCE STATEMENT The endogenous cannabinoid system plays diverse roles in brain development, which, combined with the rapidly changing legal and medical status of cannabis-related compounds, makes understanding how exogenous cannabinoids affect brain development an important biomedical objective. The cerebellum is a key brain region in a variety of neurodevelopmental disorders, and the adult cerebellum has one of the highest expression levels of CB1R, but little is known about CB1R in the developing cerebellum. Here we report a developmentally distinct expression and function of CB1R in the cerebellum, in which endogenous or exogenous activation of CB1Rs modifies afferent synaptic strength and coordinated downstream network signaling. These findings have implications for recreational and medical use of exogenous cannabinoids by pregnant and breastfeeding women.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.1931-19.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Cerebral Dopamine Neurotrophic Factor Regulates Multiple Neuronal Subtypes
           and Behavior
    • Authors: Chen, Y.-C; Baronio, D, Semenova, S, Abdurakhmanova, S, Panula, P.
      Pages: 6146 - 6164
      Abstract: Cerebral dopamine neurotrophic factor (CDNF) protects dopaminergic neurons against toxic damage in the rodent brain and is in clinical trials to treat Parkinson's disease patients. Yet the underlying mechanism is poorly understood. To examine its significance for neural circuits and behavior, we examined the development of neurotransmitter systems from larval to male adult mutant zebrafish lacking cdnf. Although a lack of cdnf did not affect overall brain dopamine levels, dopaminergic neuronal clusters showed significant abnormalities. The number of histamine neurons that surround the dopaminergic neurons was significantly reduced. Expression of tyrosine hydroxylase 2 in the brain was elevated in cdnf mutants throughout their lifespan. There were abnormally few GABA neurons in the hypothalamus in the mutant larvae, and expression of glutamate decarboxylase was reduced throughout the brain. cdnf mutant adults showed a range of behavioral phenotypes, including increased sensitivity to pentylenetetrazole-induced seizures. Shoaling behavior of mutant adults was abnormal, and they did not display social attraction to conspecifics. CDNF plays a profound role in shaping the neurotransmitter circuit structure, seizure susceptibility, and complex behaviors in zebrafish. These findings are informative for dissecting the diverse functions of this poorly understood factor in human conditions related to Parkinson's disease and complex behaviors.SIGNIFICANCE STATEMENT A zebrafish lacking cdnf grows normally and shows no overt morphologic phenotype throughout the life span. Remarkably, impaired social cohesion and increased seizure susceptibility were found in adult cdnf KO fish conceivably associated with significant changes of dopaminergic, GABAergic, and histaminergic systems in selective brain areas. These findings suggest that cdnf has broad effects on regulating neurogenesis and maturation of transmitter-specific neuronal types during development and throughout adulthood, rather than ones restricted to the dopaminergic systems.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.2636-19.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Deletion of Calcineurin in Schwann Cells Does Not Affect Developmental
           Myelination, But Reduces Autophagy and Delays Myelin Clearance after
           Peripheral Nerve Injury
    • Authors: Reed, C. B; Frick, L. R, Weaver, A, Sidoli, M, Schlant, E, Feltri, M. L, Wrabetz, L.
      Pages: 6165 - 6176
      Abstract: In the PNS, myelination occurs postnatally when Schwann cells (SCs) contact axons. Axonal factors, such as Neuregulin-1 Type III, trigger promyelinating signals that upregulate myelin genes. Neuregulin-1 Type III has been proposed to activate calcineurin signaling in immature SCs to initiate differentiation and myelination. However, little is known about the role of calcineurin in promyelinating SCs after birth. By creating a SC conditional KO of calcineurin B (CnBscko), we assessed the effects of CnB ablation on peripheral myelination after birth in both male and female mice. Surprisingly, CnBscko mice have minimal myelination defects, no alteration of myelin thickness, and normal KROX20 expression. In contrast, we did find a unique role for calcineurin in SCs after nerve injury. Following nerve crush, CnBscko mice have slower degeneration of myelin compared with WT mice. Furthermore, absence of CnB in primary SCs delays clearance of myelin debris. SCs clear myelin via autophagy and recent literature has demonstrated that calcineurin can regulate autophagy via dephosphorylation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy. We demonstrate that loss of CnB reduces autophagic flux in primary SCs, indicating a possible mechanism for impaired myelin clearance. In addition, ablation of CnB impairs TFEB translocation to the nucleus 3 d after crush, suggesting that calcineurin may regulate autophagy in SCs via TFEB activation. Together, our data indicate that calcineurin is not essential for myelination but has a novel role in myelin clearance after injury.SIGNIFICANCE STATEMENT Our data offer a novel mechanism for activation of autophagy after peripheral nerve injury. Efficient clearance of myelin after injury by Schwann cells is important for axonal regrowth and remyelination, which is one reason why the PNS is significantly better at recovery compared with the CNS. Improved understanding of myelin clearance allows for the identification of pathways that are potentially accessible to increase myelin clearance and improve remyelination and recovery. Finally, this paper clarifies the role of calcineurin in Schwann cells and myelination.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0951-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Differential Impacts of Repeated Sampling on Odor Representations by
           Genetically-Defined Mitral and Tufted Cell Subpopulations in the Mouse
           Olfactory Bulb
    • Authors: Eiting, T. P; Wachowiak, M.
      Pages: 6177 - 6188
      Abstract: Sniffing, the active control of breathing beyond passive respiration, is used by mammals to modulate olfactory sampling. Sniffing allows animals to make odor-guided decisions within ~200 ms, but animals routinely engage in bouts of high-frequency sniffing spanning several seconds; the impact of such repeated odorant sampling on odor representations remains unclear. We investigated this question in the mouse olfactory bulb (OB), where mitral and tufted cells (MTCs) form parallel output streams of odor information processing. To test the impact of repeated odorant sampling on MTC responses, we used two-photon imaging in anesthetized male and female mice to record activation of MTCs while precisely varying inhalation frequency. A combination of genetic targeting and viral expression of GCaMP6 reporters allowed us to access mitral cell (MC) and superficial tufted cell (sTC) subpopulations separately. We found that repeated odorant sampling differentially affected responses in MCs and sTCs, with MCs showing more diversity than sTCs over the same time period. Impacts of repeated sampling among MCs included both increases and decreases in excitation, as well as changes in response polarity. Response patterns across simultaneously-imaged MCs reformatted over time, with representations of different odorants becoming more distinct. Individual MCs responded differentially to changes in inhalation frequency, whereas sTC responses were more uniform over time and across frequency. Our results support the idea that MCs and TCs comprise functionally distinct pathways for odor information processing, and suggest that the reformatting of MC odor representations by high-frequency sniffing may serve to enhance the discrimination of similar odors.SIGNIFICANCE STATEMENT Repeated sampling of odorants during high-frequency respiration (sniffing) is a hallmark of active odorant sampling by mammals; however, the adaptive function of this behavior remains unclear. We found distinct effects of repeated sampling on odor representations carried by the two main output channels from the mouse olfactory bulb (OB), mitral and tufted cells (MTCs). Mitral cells (MCs) showed more diverse changes in response patterns over time as compared with tufted cells (TCs), leading to odorant representations that were more distinct after repeated sampling. These results support the idea that MTCs contribute different aspects to encoding odor information, and they indicate that MCs (but not TCs) may play a primary role in the modulation of olfactory processing by sampling behavior.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0258-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • CCKergic Tufted Cells Differentially Drive Two Anatomically Segregated
           Inhibitory Circuits in the Mouse Olfactory Bulb
    • Authors: Sun, X; Liu, X, Starr, E. R, Liu, S.
      Pages: 6189 - 6206
      Abstract: Delineation of functional synaptic connections is fundamental to understanding sensory processing. Olfactory signals are synaptically processed initially in the olfactory bulb (OB) where neural circuits are formed among inhibitory interneurons and the output neurons mitral cells (MCs) and tufted cells (TCs). TCs function in parallel with but differently from MCs and are further classified into multiple subpopulations based on their anatomic and functional heterogeneities. Here, we combined optogenetics with electrophysiology to characterize the synaptic transmission from a subpopulation of TCs, which exclusively express the neuropeptide cholecystokinin (CCK), to two groups of spatially segregated GABAergic interneurons, granule cells (GCs) and glomerular interneurons in mice of both sexes with four major findings. First, CCKergic TCs receive direct input from the olfactory sensory neurons (OSNs). This monosynaptic transmission exhibits high fidelity in response to repetitive OSN input. Second, CCKergic TCs drive GCs through two functionally distinct types of monosynaptic connections: (1) dendrodendritic synapses onto GC distal dendrites via their lateral dendrites in the superficial external plexiform layer (EPL); (2) axodendritic synapses onto GC proximal dendrites via their axon collaterals or terminals in the internal plexiform layer (IPL) on both sides of each bulb. Third, CCKergic TCs monosynaptically excite two subpopulations of inhibitory glomerular interneurons via dendrodendritic synapses. Finally, sniff-like patterned activation of CCKergic TCs induces robust frequency-dependent depression of the dendrodendritic synapses but facilitation of the axodendritic synapses. These results demonstrated important roles of the CCKergic TCs in olfactory processing by orchestrating OB inhibitory activities.SIGNIFICANCE STATEMENT Neuronal morphology and organization in the olfactory bulb (OB) have been extensively studied, however, the functional operation of neuronal interactions is not fully understood. We combined optogenetic and electrophysiological approaches to investigate the functional operation of synaptic connections between a specific population of excitatory output neuron and inhibitory interneurons in the OB. We found that these output neurons formed distinct types of synapses with two populations of spatially segregated interneurons. The functional characteristics of these synapses vary significantly depending on the presynaptic compartments so that these output neurons can dynamically rebalance inhibitory feedback or feedforward to other neurons types in the OB in response to dynamic rhythmic inputs.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0769-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Pupillary Dynamics Link Spontaneous and Task-Evoked Activations Recorded
           Directly from Human Insula
    • Authors: Kucyi, A; Parvizi, J.
      Pages: 6207 - 6218
      Abstract: Spontaneous activations within neuronal populations can emerge similarly to "task-evoked" activations elicited during cognitive performance or sensory stimulation. We hypothesized that spontaneous activations within a given brain region have comparable functional and physiological properties to task-evoked activations. Using human intracranial EEG with concurrent pupillometry in 3 subjects (2 males, 1 female), we localized neuronal populations in the dorsal anterior insular cortex that showed task-evoked activations correlating positively with the magnitude of pupil dilation during a continuous performance task. The pupillary response peaks lagged behind insular activations by several hundreds of milliseconds. We then detected spontaneous activations, within the same neuronal populations of insular cortex, that emerged intermittently during a wakeful "resting state" and that had comparable electrophysiological properties (magnitude, duration, and spectral signature) to task-evoked activations. Critically, similar to task-evoked activations, spontaneous activations systematically preceded phasic pupil dilations with a strikingly similar temporal profile. Our findings suggest similar neurophysiological profiles between spontaneous and task-evoked activations in the human insula and support a clear link between these activations and autonomic functions measured by dynamics of pupillary dilation.SIGNIFICANCE STATEMENT Most of our knowledge about activations in the human brain is derived from studies of responses to external events and experimental conditions (i.e., "task-evoked" activations). We obtained direct neural recordings from electrodes implanted in human subjects and showed that activations emerge spontaneously and have strong similarities to task-evoked activations(e.g., magnitude, temporal profile) within the same populations of neurons. Within the dorsal anterior insula, a brain region implicated in salience processing and alertness, activations that are either spontaneous or task-evoked are coupled with brief dilations of the pupil. Our findings underscore how spontaneous brain activity, a major current focus of human neuroimaging studies aimed at developing biomarkers of disease, is relevant to ongoing physiological and possibly self-generated mental processes.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.0435-20.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Neurotelemetry Reveals Putative Predictive Activity in HVC during
           Call-Based Vocal Communications in Zebra Finches
    • Authors: Ma, S; ter Maat, A, Gahr, M.
      Pages: 6219 - 6227
      Abstract: Premotor predictions facilitate vocal interactions. Here, we study such mechanisms in the forebrain nucleus HVC (proper name), a cortex-like sensorimotor area of songbirds, otherwise known for being essential for singing in zebra finches. To study the role of the HVC in calling interactions between male and female mates, we used wireless telemetric systems for simultaneous measurement of neuronal activity of male zebra finches and vocalizations of males and females that freely interact with each other. In a non-social context, male HVC neurons displayed stereotypic premotor activity in relation to active calling and showed auditory-evoked activity to hearing of played-back female calls. In a social context, HVC neurons displayed auditory-evoked activity to hearing of female calls only if that neuron showed activity preceding the upcoming female calls. We hypothesize that this activity preceding the auditory-evoked activity in the male HVC represents a neural correlate of behavioral anticipation, predictive activity that helps to coordinate vocal communication between social partners.SIGNIFICANCE STATEMENT Most social-living vertebrates produce large numbers of calls per day, and the calls have prominent roles in social interactions. Here, we show neuronal mechanisms that are active during call-based vocal communication of zebra finches, a highly social songbird species. HVC, a forebrain nucleus known for its importance in control of learned vocalizations of songbirds, displays predictive activity that may enable the male to adjust his own calling pattern to produce very fast sequences of male female call exchanges.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.2664-19.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Depression and Social Defeat Stress Are Associated with Inhibitory
           Synaptic Changes in the Nucleus Accumbens
    • Authors: Heshmati, M; Christoffel, D. J, LeClair, K, Cathomas, F, Golden, S. A, Aleyasin, H, Turecki, G, Friedman, A. K, Han, M.-H, Menard, C, Russo, S. J.
      Pages: 6228 - 6233
      Abstract: Chronic stress in both humans and rodents induces a robust downregulation of neuroligin-2, a key component of the inhibitory synapse, in the NAc that modifies behavioral coping mechanisms and stress resiliency in mice. Here we extend this observation by examining the role of two other inhibitory synapse constituents, vesicular GABA transporter (vGAT) and gephyrin, in the NAc of male mice that underwent chronic social defeat stress (CSDS) and in patients with major depressive disorder (MDD). We first performed transcriptional profiling of vGAT and gephyrin in postmortem NAc samples from a cohort of healthy controls, medicated, and nonmedicated MDD patients. In parallel, we conducted whole-cell electrophysiology recordings in the NAc of stress-susceptible and stress-resilient male mice following 10 d of CSDS. Finally, we used immunohistochemistry to analyze protein levels of vGAT and gephyrin in the NAc of mice after CSDS. We found that decreased vGAT and gephyrin mRNA in the NAc of nonmedicated MDD patients is paralleled by decreased inhibitory synapse markers and decreased frequency of mini inhibitory postsynaptic currents (mIPSC) in the NAc of susceptible mice, indicating a reduction in the number of NAc inhibitory synapses that is correlated with depression-like behavior. Overall, these findings suggest a common state of reduced inhibitory tone in the NAc in depression and stress susceptibility.SIGNIFICANCE STATEMENT Existing studies focus on excitatory synaptic changes after social stress, although little is known about stress-induced inhibitory synaptic plasticity and its relevance for neuropsychiatric disease. These results extend our previous findings on the critical role of impaired inhibitory tone in the NAc following stress and provide new neuropathological evidence for reduced levels of inhibitory synaptic markers in human NAc from nonmedicated major depressive disorder patients. This finding is corroborated in stress-susceptible male mice that have undergone chronic social defeat stress, a mouse model of depression, at both the level of synaptic function and protein expression. These data support the hypothesis that reduced inhibitory synaptic transmission within the NAc plays a critical role in the stress response.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.2568-19.2020
      Issue No: Vol. 40, No. 32 (2020)
  • Dietary Amino Acids Impact LRRK2-Induced Neurodegeneration in Parkinson's
           Disease Models
    • Authors: Chittoor-Vinod, V. G; Villalobos-Cantor, S, Roshak, H, Shea, K, Abalde-Atristain, L, Martin, I.
      Pages: 6234 - 6249
      Abstract: The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under nonpathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content in Drosophila studies with both sexes. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high-amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5'-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.SIGNIFICANCE STATEMENT Parkinson's disease (PD) prevalence is projected to rise as populations continue to age, yet there are no current therapeutic approaches that delay or stop disease progression. A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged. Here, we show that dietary amino acids are important determinants of neurodegeneration in a Drosophila model of LRRK2 PD. Restricting all amino acids effectively suppresses dopaminergic neuron loss and locomotor deficits and is associated with reduced protein synthesis, while moderately high amino acids similarly attenuate these PD-related phenotypes through a stress-responsive induction of 5'-AMP-activated protein kinase and autophagy. These studies suggest that diet plays an important role in the development of PD-related phenotypes linked to LRRK2.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.2809-19.2020
      Issue No: Vol. 40, No. 32 (2020)
  • An Astrocytic Influence on Impaired Tonic Inhibition in Hippocampal CA1
           Pyramidal Neurons in a Mouse Model of Rett Syndrome
    • Authors: Dong, Q; Kim, J, Nguyen, L, Bu, Q, Chang, Q.
      Pages: 6250 - 6261
      Abstract: Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although altered interneuron development and function are clearly demonstrated in RTT mice, a particular mode of inhibition, tonic inhibition, has not been carefully examined. We report here that tonic inhibition is significantly reduced in pyramidal neurons in the CA1 region of the hippocampus in mice where Mecp2 is deleted either in all cells or specifically in astrocytes. Since no change is detected in the level of GABA receptors, such a reduction in tonic inhibition is likely a result of decreased ambient GABA level in the extracellular space. Consistent with this explanation, we observed increased expression of a GABA transporter, GABA transporter 3 (GAT3), in the hippocampus of the Mecp2 KO mice, as well as a corresponding increase of GAT3 current in hippocampal astrocytes. These phenotypes are relevant to RTT because pharmacological blockage of GAT3 can normalize tonic inhibition and intrinsic excitability in CA1 pyramidal neurons, and rescue the phenotype of increased network excitability in acute hippocampal slices from the Mecp2 KO mice. Finally, chronic administration of a GAT3 antagonist improved a composite symptom score and extended lifespan in the Mecp2 KO mice. Only male mice were used in this study. These results not only advance our understanding of RTT etiology by defining a new neuronal phenotype and revealing how it can be influenced by astrocytic alterations, but also reveal potential targets for intervention.SIGNIFICANCE STATEMENT Our study reports a novel phenotype of reduced tonic inhibition in hippocampal CA1 pyramidal neurons in the Rett syndrome mice, reveal a potential mechanism of increased GABA transporter expression/activity in the neighboring astrocytes, describe a disease-relevant consequence in hyperexcitability, and provide preliminary evidence that targeting this phenotype may slow down disease progression in Rett syndrome mice. These results help our understanding of the disease etiology and identify a new therapeutic target for treating Rett syndrome.
      PubDate: 2020-08-05T09:30:22-07:00
      DOI: 10.1523/JNEUROSCI.3042-19.2020
      Issue No: Vol. 40, No. 32 (2020)
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