bluuebunny/crossref_metadata_2025 huggingface dataset:
Location and Function of the Slow Afterhyperpolarization Channels in the Basolateral Amygdala
Authors: Power John M. , Bocklisch Christina , Curby Peter , Sah Pankaj
Published: January 2011

The basolateral amygdala (BLA) assigns emotional significance to sensory stimuli. This association results in a change in the output (action potentials) of BLA projection neurons in response to the stimulus. Neuronal output is controlled by the intrinsic excitability of the neuron. A major determinant of intrinsic excitability in these neurons is the slow afterhyperpolarization (sAHP) that follows action potential (AP) trains and produces spike-frequency adaptation. The sAHP is mediated by a slow calcium-activated potassium current (sIAHP), but little is known about the channels that underlie this current. Here, using whole-cell patch-clamp recordings and high-speed calcium imaging from rat BLA projection neurons, we examined the location and function of these channels. We determined the location of the sIAHPby applying a hyperpolarizing voltage step during the sIAHPand measuring the time needed for the current to adapt to the new command potential, a function of its electrotonic distance from the somatic recording electrode. Channel location was also probed by focally uncaging calcium using a UV laser. Both methodologies indicated that, in BLA neurons, the sIAHPis primarily located in the dendritic tree. EPSPs recorded at the soma were smaller, decayed faster, and showed less summation during the sAHP. Adrenergic stimulation and buffering calcium reduced the sAHP and the attenuation of the EPSP during the sAHP. The sAHP also modulated the AP in the dendrite, reducing the calcium response evoked by a single AP. Thus, in addition to mediating spike-frequency adaptation, the sIAHPmodulates communication between the soma and the dendrite.
Delineating the Neural Signatures of Tracking Spatial Position and Working Memory during Attentive Tracking
Authors: Drew Trafton , Horowitz Todd S. , Wolfe Jeremy M. , Vogel Edward K.
Published: January 2011

In the attentive tracking task, observers track multiple objects as they move independently and unpredictably among visually identical distractors. Although a number of models of attentive tracking implicate visual working memory as the mechanism responsible for representing target locations, no study has ever directly compared the neural mechanisms of the two tasks. In the current set of experiments, we used electrophysiological recordings to delineate similarities and differences between the neural processing involved in working memory and attentive tracking. We found that the contralateral electrophysiological response to the two tasks was similarly sensitive to the number of items attended in both tasks but that there was also a unique contralateral negativity related to the process of monitoring target position during tracking. This signal was absent for periods of time during tracking tasks when objects briefly stopped moving. These results provide evidence that, during attentive tracking, the process of tracking target locations elicits an electrophysiological response that is distinct and dissociable from neural measures of the number of items being attended.
The Role of the Met66 Brain-Derived Neurotrophic Factor Allele in the Recovery of Executive Functioning after Combat-Related Traumatic Brain Injury
Authors: Krueger Frank , Pardini Matteo , Huey Edward D. , Raymont Vanessa , Solomon Jeffrey , Lipsky Robert H. , Hodgkinson Colin A. , Goldman David , Grafman Jordan
Published: January 2011

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the recovery of executive functioning after TBI. We genotyped a sample of male Vietnam combat veterans consisting of a frontal lobe lesion group with focal penetrating head injuries and a non-head-injured control group for the Val66Met BDNF polymorphism. The Delis–Kaplan Executive Function System as a standardized psychometric battery was administrated to examine key domains of executive functions. The results revealed that the Met allele but not the hypothesized Val allele promotes recovery of executive functioning. Overall, the Met66 carriers in the lesion group performed as well as the Met66 carriers in the control group. The Met66 allele accounted for 6.2% of variance for executive functioning independently of other significant predictors including preinjury intelligence, left hemisphere volume loss, and dorsolateral PFC volume loss. The findings point to different mechanisms of the Val66Met BDNF gene in complex phenotypes under normal and pathological conditions. A better understanding of these mechanisms could be instrumental in the development and application of effective therapeutic strategies to facilitate recovery from TBI.
Mapping Infant Brain Myelination with Magnetic Resonance Imaging
Authors: Deoni Sean C. L. , Mercure Evelyne , Blasi Anna , Gasston David , Thomson Alex , Johnson Mark , Williams Steven C. R. , Murphy Declan G. M.
Published: January 2011

Myelination, the elaboration of myelin surrounding neuronal axons, is essential for normal brain function. The development of the myelin sheath enables rapid synchronized communication across the neural systems responsible for higher order cognitive functioning. Despite this critical role, quantitative visualization of myelinationin vivois not possible with current neuroimaging techniques including diffusion tensor and structural magnetic resonance imaging (MRI). Although these techniques offer insight into structural maturation, they reflect several different facets of development, e.g., changes in axonal size, density, coherence, and membrane structure; lipid, protein, and macromolecule content; and water compartmentalization. Consequently, observed signal changes are ambiguous, hindering meaningful inferences between imaging findings and metrics of learning, behavior or cognition. Here we present the first quantitative study of myelination in healthy human infants, from 3 to 11 months of age. Using a new myelin-specific MRI technique, we report a spatiotemporal pattern beginning in the cerebellum, pons, and internal capsule; proceeding caudocranially from the splenium of the corpus callosum and optic radiations (at 3–4 months); to the occipital and parietal lobes (at 4–6 months); and then to the genu of the corpus callosum and frontal and temporal lobes (at 6–8 months). Our results also offer preliminary evidence of hemispheric myelination rate differences. This work represents a significant step forward in our ability to appreciate the fundamental process of myelination, and provides the first everin vivovisualization of myelin maturation in healthy human infancy.
Remodeling of Synaptic AMPA Receptor Subtype Alters the Probability and Pattern of Action Potential Firing
Authors: Savtchouk Iaroslav , Liu Siqiong June
Published: January 2011

Changes in the subunit composition of postsynaptic AMPA-type glutamate receptors can be induced at CNS synapses by neural activity and under certain pathological conditions. Fear-induced incorporation of GluR2-containing receptors at cerebellar synapses selectively prolongs the decay time of synaptic currents, whereas a switch from GluR2-lacking to GluR2-containing receptors induced by parallel fiber stimulation reduces the amplitude in addition to lengthening the duration of EPSCs. Although it is often assumed that these two forms of synaptic plasticity will alter action potential (AP) firing in the postsynaptic neuron, this has not been directly tested. Using a dynamic current-clamp approach, we now show that the fear-induced increase in EPSC duration increases the size of EPSPs and thereby markedly enhances the AP firing probability. In contrast, the parallel fiber stimulation-triggered switch in GluR2 expression reduces the EPSP–AP coupling because of the decrease in the synaptic current amplitude. The switch also abolished the paired-pulse facilitation that arose from an activity and spermine-dependent unblock of GluR2-lacking receptors and hence reduced the ability of paired stimuli to evoke two consecutive APs. Therefore, fear-induced incorporation of GluR2 receptors enhances the EPSP–AP coupling, but the parallel fiber stimulation-triggered switch reduces both the EPSP–AP coupling and evoked AP doublets. In contrast to long-term potentiation and depression, which modify the amplitude of synaptic currents, this activity-induced change in AMPA receptor phenotype alters synaptic conductance waveform and postsynaptic short-term plasticity. These changes modulate both the probability and pattern of evoked AP firing via a fundamentally different mechanism from long-term potentiation and long-term depression.
Online Control of Hand Trajectory and Evolution of Motor Intention in the Parietofrontal System
Authors: Archambault Philippe S. , Ferrari-Toniolo Simone , Battaglia-Mayer Alexandra
Published: January 2011

The frontal mechanisms of motor intention were studied in dorsal premotor and motor cortex of monkeys making direct reaches to visual targets and online corrections of hand trajectory, whenever a change of the target's location occurred. This study and our previous one of parietal cortex (Archambault et al., 2009) provide a picture on the evolution of motor intention and online control of movement in the parietofrontal system. In frontal cortex, significant relationships were found between neural activity and hand kinematics (position, speed, and movement direction). When a change of motor intention occurred, the activity typical of the movement to the first target smoothly evolved into that associated with the movement toward the second one, as observed during direct reaches. Under these conditions, parietal cells remained a more accurate predictor of hand trajectory than frontal ones. The time lags of neural activity with hand kinematics showed that motor, premotor, and parietal cortex were activated sequentially. After the first target's presentation and its change of location, the population activity signaled the change of motor plan before the hand moved to the initial target's position. This signaling occurred earlier in premotor than in motor and parietal cortex. Thus, premotor cortex encodes a higher-order command for the correction of motor intention, while parietal cortex seems responsible for estimating the kinematics of the motor periphery, an essential step to allow motor cortex to modify the hand trajectory. This indicates that the parietofrontal system can update an original and not-yet-accomplished motor plan during its execution.
Distinct Mechanisms for Coding of Visual Actions in Macaque Temporal Cortex
Authors: Vangeneugden Joris , De Mazière Patrick A. , Van Hulle Marc M. , Jaeggli Tobias , Van Gool Luc , Vogels Rufin
Published: January 2011

Temporal cortical neurons are known to respond to visual dynamic-action displays. Many human psychophysical and functional imaging studies examining biological motion perception have used treadmill walking, in contrast to previous macaque single-cell studies. We assessed the coding of locomotion in rhesus monkey (Macaca mulatta) temporal cortex using movies of stationary walkers, varying both form and motion (i.e., different facing directions) or varying only the frame sequence (i.e., forward vs backward walking). The majority of superior temporal sulcus and inferior temporal neurons were selective for facing direction, whereas a minority distinguished forward from backward walking. Support vector machines using the temporal cortical population responses as input classified facing direction well, but forward and backward walking less so. Classification performance for the latter improved markedly when the within-action response modulation was considered, reflecting differences in momentary body poses within the locomotion sequences. Responses to static pose presentations predicted the responses during the course of the action. Analyses of the responses to walking sequences wherein the start frame was varied across trials showed that some neurons also carried a snapshot sequence signal. Such sequence information was present in neurons that responded to static snapshot presentations and in neurons that required motion. Our data suggest that actions are analyzed by temporal cortical neurons using distinct mechanisms. Most neurons predominantly signal momentary pose. In addition, temporal cortical neurons, including those responding to static pose, are sensitive to pose sequence, which can contribute to the signaling of learned action sequences.
FoxG1 Promotes the Survival of Postmitotic Neurons
Authors: Dastidar Somasish Ghosh , Landrieu Paul Michael Zagala , D'Mello Santosh R.
Published: January 2011

The transcription factor FoxG1 regulates neurogenesis in the embryonic telencephalon as well as a number of other neurodevelopmental processes. While FoxG1 continues to be expressed in neurons postnatally and through adulthood, its role in fully differentiated neurons is not known. The current study demonstrates that FoxG1 promotes the survival of postmitotic neurons. In cerebellar granule neurons primed to undergo apoptosis, FoxG1 expression is reduced. Ectopic expression of FoxG1 blocks neuronal death, whereas suppression of its expression induces death in otherwise healthy neurons. The first 36 residues of FoxG1 are necessary for its survival-promoting effect, while the C-terminal half of the protein is dispensable. Mutation of Asp219, a residue necessary for DNA binding, abrogates survival promotion by FoxG1. Survival promotion is also eliminated by mutation of Thr271, a residue phosphorylated by Akt. Pharmacological inhibition of Akt blocks the survival effects of wild-type FoxG1 but not forms in which Thr271 is replaced with phosphomimetic residues. Treatment of neurons with IGF-1, a neurotrophic factor that promotes neuronal survival by activating Akt, prevents the apoptosis-associated downregulation of FoxG1 expression. Moreover, the overexpression of dominant-negative forms of FoxG1 blocks the ability of IGF-1 to maintain neuronal survival suggesting that FoxG1 is a downstream mediator of IGF-1/Akt signaling. Our study identifies a new and important function for FoxG1 in differentiated neurons.
Dual Regulation of Fragile X Mental Retardation Protein by Group I Metabotropic Glutamate Receptors Controls Translation-Dependent Epileptogenesis in the Hippocampus
Authors: Zhao Wangfa , Chuang Shih-Chieh , Bianchi Riccardo , Wong Robert K. S.
Published: January 2011

Group I metabotropic glutamate receptors (mGluRs) stimulation activates translation-dependent epileptogenesis in the hippocampus. This translation is regulated by repressors, including BC1 RNA and fragile X mental retardation protein (FMRP). Recent data indicate that group I mGluR stimulation exerts bidirectional control over FMRP level by activating translation and ubiquitin-proteasome system (UPS)-dependent proteolysis for the up- and downregulation of the protein, respectively. At present, the temporal relationship of translation and proteolysis on FMRP and their interplay for group I mGluR-mediated translation and epileptogenesis are unknown. We addressed these issues by using mouse hippocampal slices. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG)] stimulation of group I mGluRs caused a biphasic change in FMRP level. An initial decrease (within 10 min) was followed by an increase at 30 min. When slices were pretreated with translation inhibitor (anisomycin or cycloheximide), group I mGluRs elicited a sustained decrease in FMRP. This decrease was prevented by a proteasome inhibitor [Z-Leu-Leu-Leu-CHO (MG-132)]. When slices were pretreated with MG-132 alone, DHPG no longer elicited any change in FMRP. MG-132 also suppressed increase in other proteins, including postsynaptic density-95and α-calcium/calmodulin-dependent protein kinase II, normally elicited by group I mGluR stimulation. Physiological experiments showed that proteasome inhibitor suppressed group I mGluR-induced prolonged synchronized discharges. However, proteasome inhibitor did not affect group I mGluR-induced prolonged synchronized discharges inFmr1−/−preparations, where functional FMRP is absent. The results suggest that constitutive FMRP in hippocampal cells acts as a brake on group I mGluR-mediated translation and epileptogenesis. FMRP downregulation via UPS removes this brake enabling group I mGluR-mediated translation and epileptogenesis.
Profound Desensitization by Ambient GABA Limits Activation of δ-Containing GABAAReceptors during Spillover
Authors: Bright Damian P. , Renzi Massimiliano , Bartram Julian , McGee Thomas P. , MacKenzie Georgina , Hosie Alastair M. , Farrant Mark , Brickley Stephen G.
Published: January 2011

High-affinity extrasynaptic GABAAreceptors (GABAARs) are a prominent feature of cerebellar granule neurons and thalamic relay neurons. In both cell types, the presence of synaptic glomeruli would be expected to promote activation of these GABAARs, contributing to phasic spillover-mediated currents and tonic inhibition. However, the precise role of different receptor subtypes in these two phenomena is unclear. To address this question, we made recordings from neurons in acute brain slices from mice, and from tsA201 cells expressing recombinant GABAARs. We found that δ subunit-containing GABAARs of both cerebellar granule neurons and thalamic relay neurons of the lateral geniculate nucleus contributed to tonic conductance caused by ambient GABA but not to spillover-mediated currents. In the presence of a low “ambient” GABA concentration, recombinant “extrasynaptic” δ subunit-containing GABAARs exhibited profound desensitization, rendering them insensitive to brief synaptic- or spillover-like GABA transients. Together, our results demonstrate that phasic spillover and tonic inhibition reflect the activation of distinct receptor populations.
EMMPRIN: A Novel Regulator of Leukocyte Transmigration into the CNS in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
Authors: Agrawal Smriti M. , Silva Claudia , Tourtellotte Wallace W. , Yong V. Wee
Published: January 2011

Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a member of the Ig superfamily, with various physiological roles including the induction of matrix metalloproteinases (MMPs), leukocyte activation, and tumor progression. In this study, we illustrate a novel involvement of EMMPRIN in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We found EMMPRIN levels to be upregulated on peripheral leukocytes before onset of EAE clinical signs and on infiltrating leukocytes and resident cells within the CNS in symptomatic mice. In EAE brain sections, EMMPRIN expression was localized with MMP-9 protein and activity. The increased EMMPRIN level was also characteristic of brain samples from MS subjects, particularly in plaque-containing areas. To evaluate the implications of elevated EMMPRIN levels, we treated EAE mice with an EMMPRIN function-blocking antibody and found reduced EAE clinical severity accompanied by decreased CNS parenchymal infiltration of leukocytes. Amelioration of EAE clinical signs by the anti-EMMPRIN antibody was critically dependent on its administration around the period of onset of clinical signs, which is typically associated with significant influx of leukocytes into the CNS. Moreover, the reduction in disease severity in anti-EMMPRIN-treated mice was associated with diminished MMP proteolytic activity at the glia limitans, the final barrier before parenchymal infiltration of leukocytes. Together, our results are the first to emphasize a role for EMMPRIN in MS and EAE, whereby EMMPRIN regulates leukocyte trafficking through increasing MMP activity. These results identify EMMPRIN as a novel therapeutic target in MS.
Calcium Channels Link the Muscle-Derived Synapse Organizer Laminin β2 to Bassoon and CAST/Erc2 to Organize Presynaptic Active Zones
Authors: Chen Jie , Billings Sara E. , Nishimune Hiroshi
Published: January 2011

Synapse formation requires the organization of presynaptic active zones, the synaptic vesicle release sites, in precise apposition to postsynaptic neurotransmitter receptor clusters; however, the molecular mechanisms responsible for these processes remain unclear. Here, we show that P/Q-type and N-type voltage-dependent calcium channels (VDCCs) play essential roles as scaffolding proteins in the organization of presynaptic active zones. The neuromuscular junction of double knock-out mice for P/Q- and N-type VDCCs displayed a normal size but had significantly reduced numbers of active zones and docked vesicles and featured an attenuation of the active-zone proteins Bassoon, Piccolo, and CAST/Erc2. Consistent with this phenotype, direct interactions of the VDCC β1b or β4 subunits and the active zone-specific proteins Bassoon or CAST/Erc2 were confirmed by immunoprecipitation. A decrease in the number of active zones caused by a loss of presynaptic VDCCs resembled the pathological conditions observed in the autoimmune neuromuscular disorder Lambert–Eaton myasthenic syndrome. At the synaptic cleft of double knock-out mice, we also observed a decrease of the synaptic organizer laminin β2 protein, an extracellular ligand of P/Q- and N-type VDCCs. However, the transcription level of laminin β2 did not decrease in double knock-out mice, suggesting that the synaptic accumulation of laminin β2 protein required its interaction with presynaptic VDCCs. These results suggest that presynaptic VDCCs link the target-derived synapse organizer laminin β2 to active-zone proteins and function as scaffolding proteins to anchor active-zone proteins to the presynaptic membrane.
Neuroligin 2 Is Required for Synapse Development and Function at theDrosophilaNeuromuscular Junction
Authors: Sun Mingkuan , Xing Guanglin , Yuan Liudi , Gan Guangming , Knight David , With Sheila Irene , He Cui , Han Junhai , Zeng Xiankun , Fang Ming , Boulianne Gabrielle L. , Xie Wei
Published: January 2011

Neuroligins belong to a highly conserved family of cell adhesion molecules that have been implicated in synapse formation and function. However, the precisein vivoroles of Neuroligins remain unclear. In the present study, we have analyzed the function ofDrosophila neuroligin 2(dnl2) in synaptic development and function. We show thatdnl2is strongly expressed in the embryonic and larval CNS and at the larval neuromuscular junction (NMJ).dnl2null mutants are viable but display numerous structural defects at the NMJ, including reduced axonal branching and fewer synaptic boutons.dnl2mutants also show an increase in the number of active zones per bouton but a decrease in the thickness of the subsynaptic reticulum and length of postsynaptic densities.dnl2mutants also exhibit a decrease in the total glutamate receptor density and a shift in the subunit composition of glutamate receptors in favor of GluRIIA complexes. In addition to the observed defects in synaptic morphology, we also find thatdnl2mutants show increased transmitter release and altered kinetics of stimulus-evoked transmitter release. Importantly, the defects in presynaptic structure, receptor density, and synaptic transmission can be rescued by postsynaptic expression ofdnl2. Finally, we show thatdnl2colocalizes and binds toDrosophilaneurexin (dnrx)in vivo. However, whereas homozygous mutants for eitherdnl2ordnrxare viable, double mutants are lethal and display more severe defects in synaptic morphology. Altogether, our data show that, althoughdnl2is not absolutely required for synaptogenesis, it is required postsynaptically for synapse maturation and function.
A Corticosteroid-Responsive Transcription Factor, Promyelocytic Leukemia Zinc Finger Protein, Mediates Protection of the Cochlea from Acoustic Trauma
Authors: Peppi Marcello , Kujawa Sharon G. , Sewell William F.
Published: January 2011

Animals can be induced to resist cochlear damage associated with acoustic trauma by exposure to a variety of “conditioning” stimuli, including restraint stress, moderate level sound, heat stress, hypoxia, and corticosteroids. Here we identify in mice a corticosteroid-responsive transcription factor, PLZF (promyelocytic leukemia zinc finger protein), which mediates conditioned protection of the cochlea from acoustic trauma. PLZF mRNA levels in the cochlea are increased following conditioning stimuli, including restraint stress, dexamethasone administration, and moderate-to-high level acoustic stimulation. Heterozygous mutant (luxoid.Zbtb16LU/J) mice deficient in PLZF have hearing and responses to acoustic trauma similar to their wild type littermates but are unable to generate conditioning-induced protection from acoustic trauma. PLZF immunoreactivity is present in the spiral ganglion, lateral wall of the cochlea, and organ of Corti, all targets for acoustic trauma. PLZF is also present in the brain and PLZF mRNA in brain is elevated following conditioning stimuli. The identification of a transcription factor that mediates conditioned protection from trauma provides a tool for understanding the protective action of corticosteroids, which are widely used in treating acute hearing loss, and has relevance to understanding the role of corticosteroids in trauma protection.
Tbr1andFezf2Regulate Alternate Corticofugal Neuronal Identities during Neocortical Development
Authors: McKenna William L. , Betancourt Jennifer , Larkin Kathryn A. , Abrams Benjamin , Guo Chao , Rubenstein John L. R. , Chen Bin
Published: January 2011

The molecular mechanisms regulating fate divergence of closely related, but distinct, layer 6 corticothalamic and layer 5 subcerebral projection neurons are largely unknown. We present evidence for central transcriptional mechanisms that regulate fate specification of corticothalamic (layer 6) and subcerebral (layer 5) projection neurons. We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression ofFezf2and CTIP2. These conclusions are based on the following: (1) InTbr1−/−mice, the number of cells expressing layer 6 markers was reduced, and the number of cells expressing layer 5 markers was increased. Early-born (birthdated on E11.5) neurons ectopically expressed subcerebral neuronal markers, and extended their axons into subcerebral targets. (2) EctopicTbr1expression in layer 5 neurons prevented them from extending axons into the brainstem and the spinal cord. (3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in theFezf2gene. (4) Analysis ofFezf2mutants andTbr1−/−;Fezf2−/−compound mutants provided evidence thatFezf2blocks corticothalamic fate in layer 5 by reducingTbr1expression in subcerebral neurons. All neocortical regions appear to use this core transcriptional program to specify corticothalamic (layer 6) and subcerebral (layer 5) projection neurons.
Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease
Authors: Roberson Erik D. , Halabisky Brian , Yoo Jong W. , Yao Jinghua , Chin Jeannie , Yan Fengrong , Wu Tiffany , Hamto Patricia , Devidze Nino , Yu Gui-Qiu , Palop Jorge J. , Noebels Jeffrey L. , Mucke Lennart
Published: January 2011

Alzheimer's disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn. We showed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole-cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.
Reelin Is Required for Class-Specific Retinogeniculate Targeting
Authors: Su Jianmin , Haner Cheryl V. , Imbery Terence E. , Brooks Justin M. , Morhardt Duncan R. , Gorse Karen , Guido William , Fox Michael A.
Published: January 2011

Development of visual system circuitry requires the formation of precise synaptic connections between neurons in the retina and brain. For example, axons from retinal ganglion cells (RGCs) form synapses onto neurons within subnuclei of the lateral geniculate nucleus (LGN) [i.e., the dorsal LGN (dLGN), ventral LGN (vLGN), and intergeniculate leaflet (IGL)]. Distinct classes of RGCs project to these subnuclei: the dLGN is innervated by image-forming RGCs, whereas the vLGN and IGL are innervated by non-image-forming RGCs. To explore potential mechanisms regulating class-specific LGN targeting, we sought to identify differentially expressed targeting molecules in these LGN subnuclei. One candidate targeting molecule enriched in the vLGN and IGL during retinogeniculate circuit formation was the extracellular matrix molecule reelin. Anterograde labeling of RGC axons in mutant mice lacking functional reelin (relnrl/rl) revealed reduced patterns of vLGN and IGL innervation and misrouted RGC axons in adjacent non-retino-recipient thalamic nuclei. Using genetic reporter mice, we further demonstrated that mistargeted axons were from non-image-forming, intrinsically photosensitive RGCs (ipRGCs). In contrast to mistargeted ipRGC axons, axons arising from image-forming RGCs and layer VI cortical neurons correctly targeted the dLGN inrelnrl/rlmutants. Together, these data reveal that reelin is essential for the targeting of LGN subnuclei by functionally distinct classes of RGCs.
Development and Persistence of Limbic Epileptogenesis Are Impaired in Mice Lacking Progesterone Receptors
Authors: Reddy Doodipala Samba , Mohan Ashwin
Published: January 2011

Progesterone plays a key role in ovarian cycle-related synaptic plasticity and neuronal excitability. Progesterone receptors (PRs), which mediate the cellular actions of progesterone, are expressed in the hippocampus and other limbic regions, but their functional significance remains unknown. Here, we report a novel role of PRs as crucial mediators in the development of epileptogenesis, which is the process whereby a normal brain becomes progressively epileptic because of precipitating factors. The PR knock-out (PR−/−) mouse, which lacks both the PR-A and PR-B isoforms, exhibited an increased resistance to epileptogenesis in the hippocampus and amygdala kindling models. Lack of PRs markedly impaired the persistence of seizure expression at 4 weeks after kindling development. We further show that selective inhibition of PRs in the brain by antisense oligos or pharmacological blockade of PRs by RU-486 [11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one] resulted in a significant decrease in epileptogenesis in wild-type (PR+/+) mice. The delayed epileptogenesis in PR knock-out mice was not substantially affected by inhibition of neurosteroid synthesis. Mice lacking PRs show supersensitivity to the antiseizure responses of progesterone. Collectively, these results suggest that PRs in the hippocampus are linked to signaling pathways that control susceptibility to epileptogenesis and possibly persistence of an epileptic-like state. The PR pathway may represent a unique target for preventing or retarding epileptogenesis in females.
A Role for FE65 in Controlling GnRH-1 Neurogenesis
Authors: Forni Paolo E. , Fornaro Michele , Guénette Suzanne , Wray Susan
Published: January 2011

Gonadotropin-releasing hormone-1 (GnRH-1) neurons migrate from the nasal placode to the forebrain where they control gonadal function via the hypothalamic–pituitary–gonadal axis. The birth of GnRH-1-expressing neurons is one of the first neurogenic events in the developing nasal placode. By gene expression screening on single GnRH-1 neurons, amyloid precursor binding protein-1 (FE65) was identified in migratory GnRH-1 neurons. FE65 has been shown to modulate β1-integrin dynamics, actin cytoskeleton, cell motility, and FE65/amyloid precursor protein signaling has been described in neuro/glial cell fate determination as well as in modulating neurogenesis. Analysis of two mouse lines, one deficient for the 97 kDa FE65 isoform and a second deficient for the 97 and 60 kDa forms of FE65, showed overlapping phenotypes. In both lines, no migratory defects of the GnRH-1 neurons were observed, but a 25% increase in GnRH-1 neuronal number during embryonic development was found. Bromodeoxyuridine birth tracing and spatiotemporal tracking of GnRH-1 cell precursors demonstrated that the lack of the N-terminal portion of FE65, which includes part of the functional nuclear translocation/gene transcription domain of FE65 (WW domain), extends the timing of GnRH-1 neurogenesis in the developing nasal placode without affecting proliferation of GnRH-1 neuronal progenitors or cell death. The observed changes in the dynamics of GnRH-1 neurogenesis highlight a unique role for the 97 kDa isoform of FE65 and suggest that GnRH-1 cells, which have a short neurogenic window, originate from multipotent progenitors able to generate distinct cell types as GnRH-1 neurogenesis declines in response to environmental changes.
The RhoGAPcrossveinless-cInteracts withDystrophinand Is Required for Synaptic Homeostasis at theDrosophilaNeuromuscular Junction
Authors: Pilgram Gonneke S. K. , Potikanond Saranyapin , van der Plas Mariska C. , Fradkin Lee G. , Noordermeer Jasprina N.
Published: January 2011

Duchenne muscular dystrophy is caused by mutations in theDystrophingene and is characterized by muscle degeneration and the occurrence of mental deficits in a significant number of patients. Although Dystrophin and its closely related ortholog Utrophin are present at a variety of synapses, little is known about their roles in the nervous system. Previously, we reported that absence of postsynaptic Dystrophin from theDrosophilaneuromuscular junction (NMJ) disrupts synaptic homeostasis, resulting in increased stimulus-evoked neurotransmitter release. Here, we show that RhoGAPcrossveinless-c(cv-c), a negative regulator of Rho GTPase signaling pathways, genetically interacts withDystrophin. Electrophysiological characterization of thecv-c-deficient NMJ and the use of presynaptic- and postsynaptic-specific transgenic rescue versus RNA interference reveal that the absence of postsynapticcv-cresults in elevated evoked neurotransmitter release. Thecv-cmutant NMJ exhibits an increased number of presynaptic neurotransmitter release sites and higher probability of vesicle release without apparent changes in postsynaptic glutamate receptor numbers or function. Moreover, we find that decreasing expression of the Rho GTPaseCdc42suppresses the high neurotransmitter release in thecv-candDystrophinmutants, suggesting that Cdc42 is a substrate of Cv-c. These results indicate that Dystrophin and the Rho GTPase signaling pathway likely interact at the postsynaptic side of the NMJ to maintain synaptic homeostasis. The absence of this postsynaptic pathway results in presynaptic structural and functional alterations, suggesting that retrograde signaling mechanisms are affected.
Signals Conveyed in the Pulvinar Pathway from Superior Colliculus to Cortical Area MT
Authors: Berman Rebecca A. , Wurtz Robert H.
Published: January 2011

We previously established a functional pathway extending from the superficial layers of the superior colliculus (SC) through the inferior pulvinar (PI) to cortical area MT in the primate (Macaca mulatta). Here, we characterized the signals that this pathway conveys to cortex by recording from pulvinar neurons that we identified by microstimulation as receiving input from SC and/or projecting to MT. The basic properties of these ascending-path PI neurons resembled those of SC visual neurons. Namely, they had brisk responses to spots of light, inhibitory surrounds, and relatively large receptive fields that increased with eccentricity, as well as minimal presaccadic activity. Beyond these basic properties, there were two salient results regarding the modulatory and motion signals conveyed by this ascending pathway. First, the PI neurons appeared to convey only a subset of the modulations found in the SC: they exhibited saccadic suppression, the inhibition of activity at the time of the saccade, but did not clearly show the attentional enhancement of the visual response seen in SC. Second, directional selectivity was minimal in PI neurons belonging to the ascending path but was significantly more prominent in PI neurons receiving input from MT. This finding casts doubt on earlier assumptions that PI provides directionally selective signals to MT and instead suggests that PI derives its selectivity from MT. The identification of this pathway and its transmitted activity establishes the first functional pathway from brainstem to cortex through pulvinar and makes it possible to examine its contribution to cortical visual processing, perception, and action.
HDAC3 Is a Critical Negative Regulator of Long-Term Memory Formation
Authors: McQuown Susan C. , Barrett Ruth M. , Matheos Dina P. , Post Rebecca J. , Rogge George A. , Alenghat Theresa , Mullican Shannon E. , Jones Steven , Rusche James R. , Lazar Mitchell A. , Wood Marcelo A.
Published: January 2011

Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes transcription, whereas histone deacetylation negatively regulates transcription. The interplay between histone acetyltranserases and histone deacetylases (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual HDACs in learning and memory. We examined the role of HDAC3 in long-term memory using a combined genetic and pharmacologic approach. We used HDAC3–FLOX genetically modified mice in combination with adeno-associated virus-expressing Cre recombinase to generate focal homozygous deletions ofHdac3in area CA1 of the dorsal hippocampus. To complement this approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Immunohistochemistry showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long-term memory in a persistent manner. Next we examined expression of genes implicated in long-term memory from dorsal hippocampal punches using quantitative reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) andc-foswas significantly increased in the hippocampus of HDAC3–FLOX mice compared with wild-type controls. Memory enhancements observed in HDAC3–FLOX mice were abolished by intrahippocampal delivery ofNr4a2small interfering RNA, suggesting a mechanism by which HDAC3 negatively regulates memory formation. Together, these findings demonstrate a critical role for HDAC3 in the molecular mechanisms underlying long-term memory formation.
PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice
Authors: Hongpaisan Jarin , Sun Miao-Kun , Alkon Daniel L.
Published: January 2011

Among the pathologic hallmarks of Alzheimer's disease (AD) neurodegeneration, only synaptic loss in the brains of AD patients closely correlates with the degree of dementiain vivo. Here, we describe a molecular basis for this AD loss of synapses: pathological reduction of synaptogenic PKC isozymes and their downstream synaptogenic substrates, such as brain-derived neurotrophic factor. This reduction, particularly of PKC α and ε, occurs in association with elevation of soluble β amyloid protein (Aβ), but before the appearance of the amyloid plaques or neuronal loss in the Tg2576 AD transgenic mouse strain. Conversely, treatment of the Tg2576 mouse brain with the PKC activator, bryostatin-1, restores normal or supranormal levels of PKC α and ε, reduces the level of soluble Aβ, prevents and/or reverses the loss of hippocampal synapses, and prevents the memory impairment observed at 5 months postpartum. Similarly, the PKC ε-specific activator, DCP-LA, effectively prevents synaptic loss, amyloid plaques, and cognitive deficits (also prevented by bryostatin-1) in the much more rapidly progressing 5XFAD transgenic strain. These results suggest that synaptic loss and the resulting cognitive deficits depend on the balance between the lowering effects of Aβ on PKC α and ε versus the lowering effects of PKC on Aβ in AD transgenic mice.
Neuroinflammation Leads to Region-Dependent Alterations in Astrocyte Gap Junction Communication and Hemichannel Activity
Authors: Karpuk Nikolay , Burkovetskaya Maria , Fritz Teresa , Angle Amanda , Kielian Tammy
Published: January 2011

Inflammation attenuates gap junction (GJ) communication in cultured astrocytes. Here we used a well-characterized model of experimental brain abscess as a tool to query effects of the CNS inflammatory milieu on astrocyte GJ communication and electrophysiological properties. Whole-cell patch-clamp recordings were performed on green fluorescent protein (GFP)-positive astrocytes in acute brain slices from glial fibrillary acidic protein–GFP mice at 3 or 7 d afterStaphylococcus aureusinfection in the striatum. Astrocyte GJ communication was significantly attenuated in regions immediately surrounding the abscess margins and progressively increased to levels typical of uninfected brain with increasing distance from the abscess proper. Conversely, astrocytes bordering the abscess demonstrated hemichannel activity as evident by enhanced ethidium bromide (EtBr) uptake that could be blocked by several pharmacological inhibitors, including the connexin 43 (Cx43) mimetic peptide Gap26, carbenoxolone, the pannexin1 (Panx1) mimetic peptide10Panx1, and probenecid. However, hemichannel opening was transient with astrocytic EtBr uptake observed near the abscess at day 3 but not day 7 after infection. The region-dependent pattern of hemichannel activity at day 3 directly correlated with increases in Cx43, Cx30, Panx1, and glutamate transporter expression (gliall-glutamate transporter andl-glutamate/l-aspartate transporter) along the abscess margins. Changes in astrocyte resting membrane potential and input conductance correlated with the observed changes in GJ communication and hemichannel activity. Collectively, these findings indicate that astrocyte coupling and electrical properties are most dramatically affected near the primary inflammatory site and reveal an opposing relationship between the open states of GJ channels versus hemichannels during acute infection. This relationship may extend to other CNS diseases typified with an inflammatory component.
Genetic and clinical characteristics of patients with HNF1A gene variations from the German–Austrian DPV database
Authors: Awa W L , Thon A , Raile K , Grulich-Henn J , Meissner T , Schober E , Holl R W , _ _
Published: January 2011

Objective

To determine prevalence, genetic and phenotype characteristics of patients with hepatocyte nuclear factor-1α (HNF1A) variants in the Diabetes Patienten Verlaufsdokumenation (DPV) multicentre database and to examine the influence of HNF1A mutation type, or location on clinical phenotypes.

Patients and methods

Seventy-one DPV patients were labelled as HNF1A-MODY (MODY3). Forty-four patients carried HNF1A mutations, while 27 patients were found to have HNF1A polymorphisms only. Associations between mutation type/position and age at disease onset, HbAlc, body mass index (BMI), diagnosis, family history and treatment modality were analysed using non-parametric statistics (Wilcoxon test).

Results

Patients with HNF1A mutations were 36% male, aged 14.1±5.8 years at diagnosis, and slightly overweight (BMI-SDS: +0.8±1.1). Treatment was lifestyle intervention (20.5%), insulin (35.3%), oral anti-diabetic (OAD, 43%) and both insulin+OAD (15.9%). More patients with missense mutations (60%) than patients with nonsense mutations/frameshift (23.8%) did not use insulin (P=0.03). No differences were found with regard to mutation types, isoform or domain.

We identified several previously undescribed mutations in the cohort including c.-158insGGGTTGG in the promoter region, G31X, E41X, Q130X, L162P, R245I, A269P, S355X, Q398X, Q473X, Q495X, E508X, P588fs-insGCCA and P588fs-delAC. Patients carrying HNF1A polymorphisms were significantly younger at diagnosis than patients with HNF1A mutations (10.9±4.2 vs 14.19±5.8 years; P=0.027), and all carried I27L, S487N and A98V (n=3).

Conclusion

HNF1A-MODY is the second most frequent MODY diagnosis registered in the DPV database, and previously undescribed HNF1A mutations account for about one-third of HNF1A-MODY cases. Patients with HNF1A polymorphisms documented as HNF1A-MODY were misclassified. They may have autoantibody-negative type 1B or type 2 diabetes or may have other MODY types.
High serum adiponectin is associated with favorable lipoprotein subclass profile in 6.4-year follow-up
Authors: Vanhala Mauno , Kumpula Linda S , Soininen Pasi , Kangas Antti J , Ala-Korpela Mika , Kautiainen Hannu , Mäntyselkä Pekka , Saltevo Juha
Published: January 2011

Objective

Adiponectin is linked to a favorable lipoprotein profile, but potential longitudinal associations are not known.

Design

A population-based follow-up study of all inhabitants born in 1942, 1947, 1952, and 1957 (n=1294) in Pieksämäki, a town in Finland. Of the 690 subjects participating in both the check-ups, 228 subjects with diabetes or any medication for dyslipidemia, high blood pressure, or diabetes were excluded. The final study population consisted of 462 (182 men and 280 women) apparently healthy subjects.

Methods

Main outcome measures were lipoprotein particle sizes and concentrations, apolipoprotein A-1 (APOA1) and APOB levels at baseline and follow-up across baseline adiponectin tertiles. Serum adiponectin concentrations were determined using an enzyme immunoassay, and lipoprotein subclasses using proton nuclear magnetic resonance spectroscopy.

Results

At the second health check-up 6.4 years later, the very low-density lipoprotein particle concentration decreased across the baseline adiponectin tertiles in men from 1.04 (0.28) to 0.91 (0.29) nmol/l (P for linearity=0.011) and in women from 0.92 (0.32) to 0.80 (0.24) nmol/l (P=0.002). Correspondingly, the mean high-density lipoprotein particle size increased from 9.78 to 9.90 nm in men (P<0.006) and from 10.00 to 10.14 nm in women (P<0.001).

Conclusion

The favorable links between adiponectin and lipoproteins are detectable 6.4 years later.