scholarly journals Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3037
Author(s):  
Kristen A. McLaurin ◽  
Hailong Li ◽  
Rosemarie M. Booze ◽  
Charles F. Mactutus
Keyword(s):  
Prefrontal Cortex ◽  
Dendritic Spines ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Constitutive Expression ◽  
Neural Mechanism ◽  
Neurocognitive Impairments ◽  
Age Related ◽  
Perinatally Infected ◽  
Hiv 1

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remain understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC) in HIV-1 transgenic (Tg) and control animals. Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV.

scholarly journals Neurodevelopmental processes in the prefrontal cortex derailed by chronic HIV-1 viral protein exposure

2021 ◽  
Author(s):  
Kristen A McLaurin ◽  
Hailong Li ◽  
Rosemarie M Booze ◽  
Charles F Mactutus
Keyword(s):  
Prefrontal Cortex ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Constitutive Expression ◽  
Transgenic Animals ◽  
Neurocognitive Impairments ◽  
Age Related ◽  
Perinatally Infected ◽  
Widespread Access ◽  
Hiv 1

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remains understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC). Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. Specifically, HIV-1 transgenic rats exhibited prominent deficits in dendritic and synaptic pruning, a developmental decrease in synaptic connectivity, and an age-related decline in synaptic efficacy. Examination of dendritic spine morphology revealed an age-related population shift towards a more immature dendritic spine phenotype in HIV-1 transgenic animals. There was no compelling evidence for neuroinflammation in the mPFC during early development. Understanding the neural mechanisms underlying chronic neurocognitive impairments in pALHIV may afford a key target for innovative therapeutics and cure strategies; an urgent need given the growing population of pALHIV.

scholarly journals Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling

2016 ◽  
Author(s):  
Tharkika Nagendran ◽  
Rylan S. Larsen ◽  
Rebecca L. Bigler ◽  
Shawn B. Frost ◽  
Benjamin D. Philpot ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Spine Density ◽  
Axon Injury ◽  
Synaptic Remodeling ◽  
Nerve Tracts ◽  
Specific Increase ◽  
Microfluidic Chambers

AbstractInjury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.

scholarly journals Aging and HIV-1 alter the function of specific K+ channels in prefrontal cortex pyramidal neurons

2019 ◽  
Vol 708 ◽  
pp. 134341 ◽  
Author(s):  
Lihua Chen ◽  
Christina E. Khodr ◽  
Lena Al-Harthi ◽  
Xiu-T Hu
Keyword(s):  
Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
K Channels ◽  
Hiv 1

scholarly journals Hippocampal CA1 Pyramidal Neurons ofMecp2Mutant Mice Show a Dendritic Spine Phenotype Only in the Presymptomatic Stage

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Christopher A. Chapleau ◽  
Elena Maria Boggio ◽  
Gaston Calfa ◽  
Alan K. Percy ◽  
Maurizio Giustetto ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Mutant Mice ◽  
Spine Density ◽  
Ca1 Pyramidal Neurons ◽  
Dendritic Spine Density ◽  
Presymptomatic Stage ◽  
Deficient Mice

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations inMECP2, is the leading cause of intellectual disabilities in women. Neurons inMecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus ofMecp2tm1.1Jaemale mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1stratum radiatumof symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomaticMecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

scholarly journals Learning-Dependent Dendritic Spine Plasticity Is Reduced in the Aged Mouse Cortex

2020 ◽  
Vol 14 ◽  
Author(s):  
Lianyan Huang ◽  
Hang Zhou ◽  
Kai Chen ◽  
Xiao Chen ◽  
Guang Yang
Keyword(s):  
Motor Cortex ◽  
Motor Learning ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Learning Ability ◽  
Aged Mouse ◽  
Calcium Activity ◽  
Age Related ◽  
Old Mice ◽  
Young Mice

Aging is accompanied by a progressive decrease in learning and memory function. Synaptic loss, one of the hallmarks of normal aging, likely plays an important role in age-related cognitive decline. But little is known about the impact of advanced age on synaptic plasticity and neuronal function in vivo. In this study, we examined the structural dynamics of postsynaptic dendritic spines as well as calcium activity of layer 5 pyramidal neurons in the cerebral cortex of young and old mice. Using transcranial two-photon microscopy, we found that in both sensory and motor cortices, the elimination rates of dendritic spines were comparable between young (3–5 months) and mature adults (8–10 months), but seemed higher in old mice (>20 months), contributing to a reduction of total spine number in the old brain. During the process of motor learning, old mice compared to young mice had fewer new spines formed in the primary motor cortex. Motor training-evoked somatic calcium activity in layer 5 pyramidal neurons of the motor cortex was also lower in old than young mice, which was associated with the decline of motor learning ability during aging. Together, these results demonstrate the effects of aging on learning-dependent synapse remodeling and neuronal activity in the living cortex and suggest that synaptic deficits may contribute to age-related learning impairment.

scholarly journals Developmental Stage-dependent Persistent Impact of Propofol Anesthesia on Dendritic Spines in the Rat Medial Prefrontal Cortex

2011 ◽  
Vol 115 (2) ◽  
pp. 282-293 ◽  
Author(s):  
Adrian Briner ◽  
Irina Nikonenko ◽  
Mathias De Roo ◽  
Alexandre Dayer ◽  
Dominique Muller ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Prefrontal Cortex ◽  
Developmental Stage ◽  
Medial Prefrontal Cortex ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Postnatal Life ◽  
Spine Density ◽  
Quantitative Electron Microscopy ◽  
Dendritic Spine Density

Background Recent observations demonstrate that anesthetics rapidly impair synaptogenesis during neuronal circuitry development. Whether these effects are lasting and depend on the developmental stage at which these drugs are administered remains, however, to be explored. Methods Wistar rats received propofol anesthesia at defined developmental stages during early postnatal life. The acute and long-term effects of these treatments on neuronal cytoarchitecture were evaluated by Neurolucida and confocal microscopy analysis after iontophoretic injections of Lucifer Yellow into layer 5 pyramidal neurons in the medial prefrontal cortex. Quantitative electron microscopy was applied to investigate synapse density. Results Layer 5 pyramidal neurons of the medial prefrontal cortex displayed intense dendritic growth and spinogenesis during the first postnatal month. Exposure of rat pups to propofol at postnatal days 5 and 10 significantly decreased dendritic spine density, whereas this drug induced a significant increase in spine density when administered at postnatal days 15, 20, or 30. Quantitative electron microscopy revealed that the propofol-induced increase in spine density was accompanied by a significant increase in the number of synapses. Importantly, the propofol-induced modifications in dendritic spine densities persisted up to postnatal day 90. Conclusion These new results demonstrate that propofol anesthesia can rapidly induce significant changes in dendritic spine density and that these effects are developmental stage-dependent, persist into adulthood, and are accompanied by alterations in synapse number. These data suggest that anesthesia in the early postnatal period might permanently impair circuit assembly in the developing brain.

scholarly journals Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Farhan Ali ◽  
Danielle M. Gerhard ◽  
Katherine Sweasy ◽  
Santosh Pothula ◽  
Christopher Pittenger ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
Gabaergic Neurons ◽  
Calcium Transients ◽  
Inhibitory Mechanism ◽  
Synaptic Inputs ◽  
Aspartate Receptor ◽  
Antidepressant Effects ◽  
Cortical Interneurons

AbstractA subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine.

scholarly journals Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex

2014 ◽  
Vol 111 (10) ◽  
pp. 1960-1972 ◽  
Author(s):  
Hannah J. Seong ◽  
Rudy Behnia ◽  
Adam G. Carter
Keyword(s):  
Prefrontal Cortex ◽  
Membrane Potential ◽  
Nmda Receptors ◽  
Dendritic Spines ◽  
Pyramidal Neurons ◽  
K Channels ◽  
Two Photon ◽  
Synaptic Potentials ◽  
Ampa And Nmda Receptors ◽  
Synaptic Responses

Glutamatergic inputs onto cortical pyramidal neurons are received and initially processed at dendritic spines. AMPA and NMDA receptors generate both synaptic potentials and calcium (Ca) signals in the spine head. These responses can in turn activate a variety of Ca, sodium (Na), and potassium (K) channels at spines. In principle, the roles of these receptors and channels can be strongly regulated by the subthreshold membrane potential. However, the impact of different receptors and channels has usually been studied at the level of dendrites. Much less is known about their influence at spines, where synaptic transmission and plasticity primarily occur. Here we examine single-spine responses in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon microscopy and two-photon uncaging, we first show that synaptic potentials and Ca signals differ at resting and near-threshold potentials. We then determine how subthreshold depolarizations alter the contributions of AMPA and NMDA receptors to synaptic responses. We show that voltage-sensitive Ca channels enhance synaptic Ca signals but fail to engage small-conductance Ca-activated K (SK) channels, which require greater numbers of inputs. Finally, we establish how the subthreshold membrane potential controls the ability of voltage-sensitive Na channels and K channels to influence synaptic responses. Our findings reveal how subthreshold depolarizations promote electrical and biochemical signaling at dendritic spines by regulating the contributions of multiple glutamate receptors and ion channels.

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