In JoVE (1)

Other Publications (26)

Articles by Craig D.C. Bailey in JoVE

Other articles by Craig D.C. Bailey on PubMed

Axin Negatively Affects Tau Phosphorylation by Glycogen Synthase Kinase 3beta

Journal of Neurochemistry. Nov, 2002  |  Pubmed ID: 12421363

Glycogen synthase kinase 3beta (GSK3beta) is an essential protein kinase that regulates numerous functions within the cell. One critically important substrate of GSK3beta is the microtubule-associated protein tau. Phosphorylation of tau by GSK3beta decreases tau-microtubule interactions. In addition to phosphorylating tau, GSK3beta is a downstream regulator of the wnt signaling pathway, which maintains the levels of beta-catenin. Axin plays a central role in regulating beta-catenin levels by bringing together GSK3beta and beta-catenin and facilitating the phosphorylation of beta-catenin, targeting it for ubiquitination and degradation by the proteasome. Although axin clearly facilitates the phosphorylation of beta-catenin, its effects on the phosphorylation of other GSK3beta substrates are unclear. Therefore in this study the effects of axin on GSK3beta-mediated tau phosphorylation were examined. The results clearly demonstrate that axin is a negative regulator of tau phosphorylation by GSK3beta. This negative regulation of GSK3beta-mediated tau phosphorylation is due to the fact that axin efficiently binds GSK3beta but not tau and thus sequesters GSK3beta away from tau, as an axin mutant that does not bind GSK3beta did not inhibit tau phosphorylation by GSK3beta. This is the first demonstration that axin negatively affects the phosphorylation of a GSK3beta substrate, and provides a novel mechanism by which tau phosphorylation and function can be regulated within the cell.

Tau, Where Are We Now?

Journal of Alzheimer's Disease : JAD. Oct, 2002  |  Pubmed ID: 12446970

Tau is a multifunctional protein that was originally identified as a microtubule-associated protein. Tau is primarily a neuronal protein, but it is becoming increasingly evident that tau is present in non-neuronal cells where it also plays important roles. Tau is the primary protein component of the filaments (both paired helical and straight filaments) found in Alzheimer's disease brain. Further there is an ever growing family of neurodegenerative diseases called "tauopathies" where tau pathology is the primary, defining characteristic with little or no Abeta pathology. These findings, along with the fact that mutations in the tau gene cause a group of diseases collectively known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), clearly demonstrate that tau dysfunction results in neuronal dysfunction and death. This review highlights recent findings concerning the normal metabolism and function of tau, as well as the abnormal processing and function of tau in Alzheimer's disease and in the tauopathies, both sporadic and familial.

Chronic Prenatal Ethanol Exposure Alters Ionotropic Glutamate Receptor Subunit Protein Levels in the Adult Guinea Pig Cerebral Cortex

Alcoholism, Clinical and Experimental Research. Apr, 2003  |  Pubmed ID: 12711930

The superfamily of glutamate-gated ion channels mediates fast excitatory synaptic transmission in the central nervous system and is composed of the NMDA, AMPA, and kainate receptors. Binding studies have shown that chronic prenatal and/or neonatal ethanol exposure produces persistent effects on the numbers of some of these channels. However, whether or not this chronic ethanol exposure produces long-lasting effects on the expression of specific ionotropic receptor subunits remains an open question.

The P38 MAP Kinase Signaling Pathway in Alzheimer's Disease

Experimental Neurology. Oct, 2003  |  Pubmed ID: 14552867

Chronic Prenatal Ethanol Exposure Alters the Proportion of GABAergic Neurons in Layers II/III of the Adult Guinea Pig Somatosensory Cortex

Neurotoxicology and Teratology. Jan-Feb, 2004  |  Pubmed ID: 15001214

Chronic prenatal ethanol exposure increases the expression of gamma-aminobutyric acid type A (GABA(A)) receptors in the adult guinea pig cerebral cortex. One possible explanation for this change in receptor number is the loss of GABAergic innervation and subsequent up-regulation of GABA(A) receptors. We tested this hypothesis by determining the relative proportion of glutamic acid decarboxylase (GAD) immunopositive cells in the cerebral cortex of adult guinea pig offspring that had received chronic daily exposure to ethanol (4 g/kg maternal body weight) throughout gestation. Chronic prenatal exposure to ethanol decreased the number of neurons that were GAD-immunopositive relative to the total number of cresyl-violet-stained neurons by approximately 30% in layers II/III of the adult guinea pig somatosensory cortex. No changes were observed in other cortical layers. These data suggest that chronic prenatal exposure to ethanol results in either a selective loss of GABAergic interneurons or failure to express GAD in layers II/III of the adult guinea pig somatosensory cortex.

Validity of Mouse Models for the Study of Tissue Transglutaminase in Neurodegenerative Diseases

Molecular and Cellular Neurosciences. Mar, 2004  |  Pubmed ID: 15033177

Tissue transglutaminase (tTG) is a multifunctional enzyme that catalyzes peptide cross-linking and polyamination reactions, and also is a signal-transducing GTPase. tTG protein content and enzymatic activity are upregulated in the brain in Huntington's disease and in other neurological diseases and conditions. Since mouse models are currently being used to study the role of tTG in Huntington's disease and other neurodegenerative diseases, it is critical that the level of its expression in the mouse forebrain be determined. In contrast to human forebrain where tTG is abundant, tTG can only be detected in mouse forebrain by immunoblotting a GTP-binding-enriched protein fraction. tTG mRNA content and transamidating activity are approximately 70% lower in mouse than in human forebrain. However, tTG contributes to the majority of transglutaminase activity within mouse forebrain. Thus, although tTG is expressed at lower levels in mouse compared with human forebrain, it likely plays important roles in neuronal function.

Developmental Regulation of Tissue Transglutaminase in the Mouse Forebrain

Journal of Neurochemistry. Dec, 2004  |  Pubmed ID: 15584913

Tissue transglutaminase (tTG) is a multifunctional enzyme that catalyzes both transamidation and GTPase reactions. In cell culture models tTG-mediated transamidation positively regulates many processes that occur in vivo during the mammalian brain growth spurt (BGS), including neuronal differentiation, neurite outgrowth, synaptogenesis and cell death mechanisms. However, little is known about the levels of tTG expression and transglutaminase (TG) activity during mammalian brain development. In this study, C57BL/6 mouse forebrains were collected at embryonic day (E) 12, E14, E17, postnatal day (P) 0, P7 and P56 and analyzed for tTG expression and TG activity. RT-PCR analysis demonstrated that tTG mRNA content increases during mouse forebrain development, whereas immunoblot analysis demonstrated that tTG protein content decreases during this time. TG activity was low in prenatal mouse forebrain but increased fivefold to peak at P0, which corresponds with the beginning of the mouse BGS. Further analysis demonstrated that the lack of temporal correlation between tTG protein content and TG activity is the result of an endogenous inhibitor of tTG that is present in prenatal but not postnatal mouse forebrain. These results demonstrate for the first time that tTG enzymatic activity in the mammalian forebrain is developmentally regulated by post-translational mechanisms.

Tissue Transglutaminase Contributes to Disease Progression in the R6/2 Huntington's Disease Mouse Model Via Aggregate-independent Mechanisms

Journal of Neurochemistry. Jan, 2005  |  Pubmed ID: 15606898

Huntington's disease (HD) is caused by an expansion of CAG repeats within the huntingtin gene and is characterized by intraneuronal mutant huntingtin protein aggregates. In order to determine the role of tissue transglutaminase (tTG) in HD aggregate formation and disease progression, we cross-bred the R6/2 HD mouse model with a tTG knockout mouse line. R6/2 mice that were tTG heterozygous knockouts (R6/2 : tTG+/-) and tTG homozygous knockouts (R6/2 : tTG-/-) showed a very similar increase in aggregate number within the striatum compared with R6/2 mice that were wild-type with respect to tTG (R6/2 : tTG+/+). Interestingly, a significant delay in the onset of motor dysfunction and death occurred in R6/2 : tTG-/- mice compared with both R6/2 : tTG+/+ and R6/2 : tTG+/- mice. As aggregate number was similarly increased in the striatum of both R6/2 : tTG+/- and R6/2 : tTG-/- mice, whereas only R6/2 : tTG-/- mice showed delayed disease progression, these data suggest that the contribution of tTG towards motor dysfunction and death in the R6/2 mouse is independent of its ability to negatively regulate aggregate formation. Moreover, the combined results from this study suggest that the formation of striatal huntingtin aggregates does not directly influence motor dysfunction or death in this HD mouse model.

Transglutaminases in Neurodegenerative Disorders

Progress in Experimental Tumor Research. 2005  |  Pubmed ID: 15746534

Cystamine Treatment is Neuroprotective in the YAC128 Mouse Model of Huntington Disease

Journal of Neurochemistry. Oct, 2005  |  Pubmed ID: 16181425

Huntington disease (HD) is an adult onset neurodegenerative disorder characterized by selective atrophy and cell loss within the striatum. There is currently no treatment that can prevent the striatal neuropathology. Transglutaminase (TG) activity is increased in HD patients, is associated with cell death, and has been suggested to contribute to striatal neuronal loss in HD. This work assesses the therapeutic potential of cystamine, an inhibitor of TG activity with additional potentially beneficial effects. Specifically, we examine the effect of cystamine on striatal neuronal loss in the YAC128 mouse model of HD. We demonstrate here for the first time that YAC128 mice show a forebrain-specific increase in TG activity compared with wild-type (WT) littermates which is decreased by oral delivery of cystamine. Treatment of symptomatic YAC128 mice with cystamine starting at 7 months prevented striatal neuronal loss. Cystamine treatment also ameliorated the striatal volume loss and striatal neuronal atrophy observed in these animals, but was unable to prevent motor dysfunction or the down-regulation of dopamine and cyclic adenosine monophsophate-regulated phosphoprotein (DARPP-32) expression in the striatum. While the exact mechanism responsible for the beneficial effects of cystamine in YAC128 mice is uncertain, our findings suggest that cystamine is neuroprotective and may be beneficial in the treatment of HD.

The Protective Effects of Cystamine in the R6/2 Huntington's Disease Mouse Involve Mechanisms Other Than the Inhibition of Tissue Transglutaminase

Neurobiology of Aging. Jun, 2006  |  Pubmed ID: 15896882

Tissue transglutaminase (tTG) is a multifunctional enzyme that contributes to disease progression in mouse models of Huntington's disease (HD), an inherited neurodegenerative disease that shows an age-related onset. Moreover, administration of the transglutaminase inhibitor cystamine delays the onset of pathology in the R6/2 HD mouse model. However, the contribution of tTG inhibition towards the therapeutic effects of cystamine has not been determined, as this compound likely has multiple mechanisms of action in the R6/2 mouse. In this study, we found that administration of cystamine in drinking water delayed the age of onset for motor dysfunction and extended lifespan to a similar extent in R6/2 mice that had a normal genetic complement of tTG compared with R6/2 mice that did not express tTG. Since the magnitude of cystamine's therapeutic effects was not affected by the genetic deletion of tTG, these results suggest that the mechanism of action for cystamine in this HD mouse model involves targets other than tTG inhibition.

Transglutaminase 2 Protects Against Ischemic Insult, Interacts with HIF1beta, and Attenuates HIF1 Signaling

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. Aug, 2008  |  Pubmed ID: 18375543

Transglutaminase 2 (TG2) is a multifunctional enzyme that has been implicated in the pathogenesis of neurodegenerative diseases, ischemia, and stroke. The mechanism by which TG2 modulates disease progression have not been elucidated. In this study we investigate the role of TG2 in the cellular response to ischemia and hypoxia. TG2 is up-regulated in neurons exposed to oxygen and glucose deprivation (OGD), and increased TG2 expression protects neurons against OGD-induced cell death independent of its transamidating activity. We identified hypoxia inducible factor 1beta (HIF1beta) as a TG2 binding partner. HIF1beta and HIF1alpha together form the heterodimeric transcription factor hypoxia inducible factor 1 (HIF1). TG2 and the transaminase-inactive mutant C277S-TG2 inhibited a HIF-dependent transcription reporter assay under hypoxic conditions without affecting nuclear protein levels for HIF1alpha or HIF1beta, their ability to form the HIF1 heterodimeric transcription factor, or HIF1 binding to its DNA response element. Interestingly, TG2 attenuates the up-regulation of the HIF-dependent proapoptotic gene Bnip3 in response to OGD but had no effect on the expression of VEGF, which has been linked to prosurvival processes. This study demonstrates for the first time that TG2 protects against OGD, interacts with HIF1beta, and attenuates the HIF1 hypoxic response pathway. These results indicate that TG2 may play an important role in protecting against the delayed neuronal cell death in ischemia and stroke.

Developmental Sex Differences in Nicotinic Currents of Prefrontal Layer VI Neurons in Mice and Rats

PloS One. 2010  |  Pubmed ID: 20174655

There is a large sex difference in the prevalence of attention deficit disorder; yet, relatively little is known about sex differences in the development of prefrontal attention circuitry. In male rats, nicotinic acetylcholine receptors excite corticothalamic neurons in layer VI, which are thought to play an important role in attention by gating the sensitivity of thalamic neurons to incoming stimuli. These nicotinic currents in male rats are significantly larger during the first postnatal month when prefrontal circuitry is maturing. The present study was undertaken to investigate whether there are sex differences in the nicotinic currents in prefrontal layer VI neurons during development.

The Nicotinic Acetylcholine Receptor Alpha5 Subunit Plays a Key Role in Attention Circuitry and Accuracy

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Jul, 2010  |  Pubmed ID: 20610759

Stimulation of the prefrontal cortex by acetylcholine is critical for attention; however, the cellular mechanisms underlying its influence on attention pathways within the brain are not well understood. Pyramidal neurons in layer VI of the prefrontal cortex are believed to play an important role in this process because they are excited by acetylcholine and provide a major source of feedback projections to the thalamus. Here, we show using whole-cell electrophysiology that the relatively rare alpha5 subunit of the nicotinic acetylcholine receptor powerfully enhances nicotinic currents in layer VI pyramidal neurons in prefrontal cortical brain slices from adult mice. In addition, behavioral experiments using the five-choice serial reaction time test show that the presence of the nicotinic receptor alpha5 subunit also increases the accuracy of adult mice on this visual attention task under highly demanding conditions. Together, these findings demonstrate a novel and important role for the nicotinic receptor alpha5 subunit in adult brain circuitry required for attentional performance.

Plasticity of Prefrontal Attention Circuitry: Upregulated Muscarinic Excitability in Response to Decreased Nicotinic Signaling Following Deletion of α5 or β2 Subunits

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Nov, 2011  |  Pubmed ID: 22072695

Attention depends on cholinergic stimulation of nicotinic and muscarinic acetylcholine receptors in the medial prefrontal cortex. Pyramidal neurons in layer VI of this region express cholinergic receptors of both families and play an important role in attention through their feedback projections to the thalamus. Here, we investigate how nicotinic and muscarinic cholinergic receptors affect the excitability of these neurons using whole-cell recordings in acute brain slices of prefrontal cortex. Since attention deficits have been documented in both rodents and humans having genetic abnormalities in nicotinic receptors, we focus in particular on how the cholinergic excitation of layer VI neurons is altered by genetic deletion of either of two key nicotinic receptor subunits, the accessory α5 subunit or the ligand-binding β2 subunit. We find that the cholinergic excitation of layer VI neurons is dominated by nicotinic receptors in wild-type mice and that the reduction or loss of this nicotinic stimulation is accompanied by a surprising degree of plasticity in excitatory muscarinic receptors. These findings suggest that disrupting nicotinic receptors fundamentally alters the mechanisms and timing of excitation in prefrontal attentional circuitry.

Nicotinic α5 Subunits Drive Developmental Changes in the Activation and Morphology of Prefrontal Cortex Layer VI Neurons

Biological Psychiatry. Jan, 2012  |  Pubmed ID: 22030359

Nicotinic signaling in prefrontal layer VI pyramidal neurons is important to the function of mature attention systems. The normal incorporation of α5 subunits into α4β2* nicotinic acetylcholine receptors augments nicotinic signaling in these neurons and is required for normal attention performance in adult mice. However, the role of α5 subunits in the development of the prefrontal cortex is not known.

The Native Serotonin 5-HT(5A) Receptor: Electrophysiological Characterization in Rodent Cortex and 5-HT(1A)-mediated Compensatory Plasticity in the Knock-out Mouse

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Apr, 2012  |  Pubmed ID: 22539842

The 5-HT(5A) receptor is the least understood serotonin (5-HT) receptor. Here, we electrophysiologically identify and characterize a native 5-HT(5A) receptor current in acute ex vivo brain slices of adult rodent prefrontal cortex. In the presence of antagonists for the previously characterized 5-HT(1A) and 5-HT₂ receptors, a proportion of layer V pyramidal neurons continue to show 5-HT-elicited outward currents in both rats and mice. These 5-HT currents are suppressed by the selective 5-HT(5A) antagonist, SB-699551, and are not observed in 5-HT(5A) receptor knock-out mice. Further characterization reveals that the 5-HT(5A) current is activated by submicromolar concentrations of 5-HT, is inwardly rectifying with a reversal potential near the equilibrium potential for K+ ions, and is suppressed by blockers of Kir3 channels. Finally, we observe that genetic deletion of the inhibitory 5-HT(5A) receptor results in an unexpected, large increase in the inhibitory 5-HT(1A) receptor currents. The presence of functional prefrontal 5-HT(5A) receptors in normal rodents along with compensatory plasticity in 5-HT(5A) receptor knock-out mice testifies to the significance of this receptor in the healthy prefrontal cortex.

Chrna5 Genotype Determines the Long-lasting Effects of Developmental in Vivo Nicotine Exposure on Prefrontal Attention Circuitry

Neuropharmacology. Feb, 2014  |  Pubmed ID: 24055499

Maternal smoking during pregnancy repeatedly exposes the developing fetus to nicotine and is linked with attention deficits in offspring. Corticothalamic neurons within layer VI of the medial prefrontal cortex are potential targets in the disruption of attention circuitry by nicotine, a process termed teratogenesis. These prefrontal layer VI neurons would be likely targets because they are developmentally excited and morphologically sculpted by a population of nicotinic acetylcholine receptors (nAChRs) that are sensitive to activation and/or desensitization by nicotine. The maturational effects of these α4β2* nAChRs and their susceptibility to desensitization are both profoundly altered by the incorporation of an α5 subunit, encoded by the chrna5 gene. Here, we investigate nicotine teratogenesis in layer VI neurons of wildtype and α5(-/-) mice. In vivo chronic nicotine exposure during development significantly modified apical dendrite morphology and nAChR currents, compared with vehicle control. The direction of the changes was dependent on chrna5 genotype. Surprisingly, neurons from wildtype mice treated with in vivo nicotine resembled those from α5(-/-) mice treated with vehicle, maintaining into adulthood a morphological phenotype characteristic of immature mice together with reduced nAChR currents. In α5(-/-) mice, however, developmental in vivo nicotine tended to normalize both adult morphology and nAChR currents. These findings suggest that chrna5 genotype can determine the effect of developmental in vivo nicotine on the prefrontal cortex. In wildtype mice, the lasting alterations to the morphology and nAChR activation of prefrontal layer VI neurons are teratogenic changes consistent with the attention deficits observed following developmental nicotine exposure.

Nicotinic Acetylcholine Receptors in Attention Circuitry: the Role of Layer VI Neurons of Prefrontal Cortex

Cellular and Molecular Life Sciences : CMLS. Apr, 2014  |  Pubmed ID: 24122021

Cholinergic modulation of prefrontal cortex is essential for attention. In essence, it focuses the mind on relevant, transient stimuli in support of goal-directed behavior. The excitation of prefrontal layer VI neurons through nicotinic acetylcholine receptors optimizes local and top-down control of attention. Layer VI of prefrontal cortex is the origin of a dense feedback projection to the thalamus and is one of only a handful of brain regions that express the α5 nicotinic receptor subunit, encoded by the gene chrna5. This accessory nicotinic receptor subunit alters the properties of high-affinity nicotinic receptors in layer VI pyramidal neurons in both development and adulthood. Studies investigating the consequences of genetic deletion of α5, as well as other disruptions to nicotinic receptors, find attention deficits together with altered cholinergic excitation of layer VI neurons and aberrant neuronal morphology. Nicotinic receptors in prefrontal layer VI neurons play an essential role in focusing attention under challenging circumstances. In this regard, they do not act in isolation, but rather in concert with cholinergic receptors in other parts of prefrontal circuitry. This review urges an intensification of focus on the cellular mechanisms and plasticity of prefrontal attention circuitry. Disruptions in attention are one of the greatest contributing factors to disease burden in psychiatric and neurological disorders, and enhancing attention may require different approaches in the normal and disordered prefrontal cortex.

Cholinergic Excitation in Mouse Primary Vs. Associative Cortex: Region-specific Magnitude and Receptor Balance

The European Journal of Neuroscience. Aug, 2014  |  Pubmed ID: 24827827

Cholinergic stimulation of the cerebral cortex is essential for tasks requiring attention; however, there is still some debate over which cortical regions are required for such tasks. There is extensive cholinergic innervation of both primary and associative cortices, and transient release of acetylcholine (ACh) is detected in deep layers of the relevant primary and/or associative cortex, depending on the nature of the attention task. Here, we investigated the electrophysiological effects of ACh in layer VI, the deepest layer, of the primary somatosensory cortex, the primary motor cortex, and the associative medial prefrontal cortex. Layer VI pyramidal neurons are a major source of top-down modulation of attention, and we found that the strength and homogeneity of their direct cholinergic excitation was region-specific. On average, neurons in the primary cortical regions showed weaker responses to ACh, mediated by a balance of contributions from both nicotinic and muscarinic ACh receptors. Conversely, neurons in the associative medial prefrontal cortex showed significantly stronger excitation by ACh, mediated predominantly by nicotinic receptors. The greatest diversity of responses to ACh was found in the primary somatosensory cortex, with only a subset of neurons showing nicotinic excitation. In a mouse model with attention deficits only under demanding conditions, cholinergic excitation was preserved in primary cortical regions but not in the associative medial prefrontal cortex. These findings demonstrate that the effect of ACh is not uniform throughout the cortex, and suggest that its ability to enhance attention performance may involve different cellular mechanisms across cortical regions.

Dendritic Spine Density of Prefrontal Layer 6 Pyramidal Neurons in Relation to Apical Dendrite Sculpting by Nicotinic Acetylcholine Receptors

Frontiers in Cellular Neuroscience. 2015  |  Pubmed ID: 26500498

Prefrontal layer 6 (L6) pyramidal neurons play an important role in the adult control of attention, facilitated by their strong activation by nicotinic acetylcholine receptors. These neurons in mouse association cortex are distinctive morphologically when compared to L6 neurons in primary cortical regions. Roughly equal proportions of the prefrontal L6 neurons have apical dendrites that are "long" (reaching to the pial surface) vs. "short" (terminating in the deep layers, as in primary cortical regions). This distinct prefrontal morphological pattern is established in the post-juvenile period and appears dependent on nicotinic receptors. Here, we examine dendritic spine densities in these two subgroups of prefrontal L6 pyramidal neurons under control conditions as well as after perturbation of nicotinic acetylcholine receptors. In control mice, the long neurons have significantly greater apical and basal dendritic spine density compared to the short neurons. Furthermore, manipulations of nicotinic receptors (chrna5 deletion or chronic developmental nicotine exposure) have distinct effects on these two subgroups of L6 neurons: apical spine density is significantly reduced in long neurons, and basal spine density is significantly increased in short neurons. These changes appear dependent on the α5 nicotinic subunit encoded by chrna5. Overall, the two subgroups of prefrontal L6 neurons appear positioned to integrate information either across cortex (long neurons) or within the deep layers (short neurons), and nicotinic perturbations differently alter spine density within each subgroup.

Rapid Increases in Immature Synapses Parallel Estrogen-induced Hippocampal Learning Enhancements

Proceedings of the National Academy of Sciences of the United States of America. Dec, 2015  |  Pubmed ID: 26655342

Dramatic increases in hippocampal spine synapse density are known to occur within minutes of estrogen exposure. Until now, it has been assumed that enhanced spinogenesis increased excitatory input received by the CA1 pyramidal neurons, but how this facilitated learning and memory was unclear. Delivery of 17β-estradiol or an estrogen receptor (ER)-α (but not ER-β) agonist into the dorsal hippocampus rapidly improved general discrimination learning in female mice. The same treatments increased CA1 dendritic spines in hippocampal sections over a time course consistent with the learning acquisition phase. Surprisingly, estrogen-activated spinogenesis was associated with a decrease in CA1 hippocampal excitatory input, rapidly and transiently reducing CA1 AMPA activity via a mechanism likely reflecting AMPA receptor internalization and creation of silent or immature synapses. We propose that estrogens promote hippocampally mediated learning via a mechanism resembling some of the broad features of normal development, an initial overproduction of functionally immature connections being subsequently "pruned" by experience.

Postsynaptic Nicotinic Acetylcholine Receptors Facilitate Excitation of Developing CA1 Pyramidal Neurons

Journal of Neurophysiology. Nov, 2016  |  Pubmed ID: 27489367

The hippocampus plays a key role in learning and memory. The normal development and mature function of hippocampal networks supporting these cognitive functions depends on afferent cholinergic neurotransmission mediated by nicotinic acetylcholine receptors. Whereas it is well-established that nicotinic receptors are present on GABAergic interneurons and on glutamatergic presynaptic terminals within the hippocampus, the ability of these receptors to mediate postsynaptic signaling in pyramidal neurons is not well understood. We use whole cell electrophysiology to show that heteromeric nicotinic receptors mediate direct inward currents, depolarization from rest and enhanced excitability in hippocampus CA1 pyramidal neurons of male mice. Measurements made throughout postnatal development provide a thorough developmental profile for these heteromeric nicotinic responses, which are greatest during the first 2 wk of postnatal life and decrease to low adult levels shortly thereafter. Pharmacological experiments show that responses are blocked by a competitive antagonist of α4β2* nicotinic receptors and augmented by a positive allosteric modulator of α5 subunit-containing receptors, which is consistent with expression studies suggesting the presence of α4β2 and α4β2α5 nicotinic receptors within the developing CA1 pyramidal cell layer. These findings demonstrate that functional heteromeric nicotinic receptors are present on CA1 pyramidal neurons during a period of major hippocampal development, placing these receptors in a prime position to play an important role in the establishment of hippocampal cognitive networks.

Developmental Ethanol Exposure Leads to Long-Term Deficits in Attention and Its Underlying Prefrontal Circuitry

ENeuro. Sep-Oct, 2016  |  Pubmed ID: 27844059

Chronic prenatal exposure to ethanol can lead to a spectrum of teratogenic outcomes that are classified in humans as fetal alcohol spectrum disorders (FASD). One of the most prevalent and persistent neurocognitive components of FASD is attention deficits, and it is now thought that these attention deficits differ from traditional attention deficit hyperactivity disorder (ADHD) in their quality and response to medication. However, the neuronal mechanisms underlying attention deficits in FASD are not well understood. We show here that after developmental binge-pattern ethanol exposure, adult mice exhibit impaired performance on the five-choice serial reaction time test for visual attention, with lower accuracy during initial training and a higher rate of omissions under challenging conditions of high attention demand. Whole-cell electrophysiology experiments in these same mice find dysregulated pyramidal neurons in layer VI of the medial prefrontal cortex, which are critical for normal attention performance. Layer VI neurons show decreased intrinsic excitability and increased responses to stimulation of both nicotinic acetylcholine receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Moreover, although nicotinic acetylcholine responses correlate with performance on the five-choice task in control mice, these relationships are completely disrupted in mice exposed to ethanol during development. These findings demonstrate a novel outcome of developmental binge-pattern ethanol exposure and suggest that persistent alterations to the function of prefrontal layer VI neurons play an important mechanistic role in attention deficits associated with FASD.

A Novel Multisensory Integration Task Reveals Robust Deficits in Rodent Models of Schizophrenia: Converging Evidence for Remediation Via Nicotinic Receptor Stimulation of Inhibitory Transmission in the Prefrontal Cortex

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience. Dec, 2016  |  Pubmed ID: 27974613

Atypical multisensory integration is an understudied cognitive symptom in schizophrenia. Procedures to evaluate multisensory integration in rodent models are lacking. We developed a novel multisensory object oddity (MSO) task to assess multisensory integration in ketamine-treated rats, a well established model of schizophrenia. Ketamine-treated rats displayed a selective MSO task impairment with tactile-visual and olfactory-visual sensory combinations, whereas basic unisensory perception was unaffected. Orbitofrontal cortex (OFC) administration of nicotine or ABT-418, an α4β2 nicotinic acetylcholine receptor (nAChR) agonist, normalized MSO task performance in ketamine-treated rats and this effect was blocked by GABAA receptor antagonism. GABAergic currents were also decreased in OFC of ketamine-treated rats and were normalized by activation of α4β2 nAChRs. Furthermore, parvalbumin (PV) immunoreactivity was decreased in the OFC of ketamine-treated rats. Accordingly, silencing of PV interneurons in OFC of PV-Cre mice using DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) selectively impaired MSO task performance and this was reversed by ABT-418. Likewise, clozapine-N-oxide-induced inhibition of PV interneurons in brain slices was reversed by activation of α4β2 nAChRs. These findings strongly imply a role for prefrontal GABAergic transmission in the integration of multisensory object features, a cognitive process with relevance to schizophrenia. Accordingly, nAChR agonism, which improves various facets of cognition in schizophrenia, reversed the severe MSO task impairment in this study and appears to do so via a GABAergic mechanism. Interactions between GABAergic and nAChR receptor systems warrant further investigation for potential therapeutic applications. The novel behavioral procedure introduced in the current study is acutely sensitive to schizophrenia-relevant cognitive impairment and should prove highly valuable for such research.

Expansion of Mossy Fibers and CA3 Apical Dendritic Length Accompanies the Fall in Dendritic Spine Density After Gonadectomy in Male, but Not Female, Rats

Brain Structure & Function. Jan, 2017  |  Pubmed ID: 27283589

Androgen loss is an important clinical concern because of its cognitive and behavioral effects. Changes in androgen levels are also suspected to contribute to neurological disease. However, the available data on the effects of androgen deprivation in areas of the brain that are central to cognition, like the hippocampus, are mixed. In this study, morphological analysis of pyramidal cells was used to investigate if structural changes could potentially contribute to the mixed cognitive effects that have been observed after androgen loss in males. Male Sprague-Dawley rats were orchidectomized or sham-operated. Two months later, their brains were Golgi-impregnated for morphological analysis. Morphological endpoints were studied in areas CA3 and CA1, with comparisons to females either intact or 2 months after ovariectomy. CA3 pyramidal neurons of orchidectomized rats exhibited marked increases in apical dendritic arborization. There were increases in mossy fiber afferent density in area CA3, as well as robust enhancements to dendritic structure in area CA3 of orchidectomized males, but not in CA1. Remarkably, apical dendritic length of CA3 pyramidal cells increased, while spine density declined. By contrast, in females overall dendritic structure was minimally affected by ovariectomy, while dendritic spine density was greatly reduced. Sex differences and subfield-specific effects of gonadal hormone deprivation on the hippocampal circuitry may help explain the different behavioral effects reported in males and females after gonadectomy, or other conditions associated with declining gonadal hormone secretion.

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