Boys-Specific Text-Comprehension Enhancement With Dual Visual-Auditory Text Presentation Among 12-14 Years-Old Students.

Quality of language comprehension determines performance in all kinds of activities including academics. Processing of words initially develops as auditory, and gradually extends to visual as children learn to read. School failure is highly related to listening and reading comprehension problems. In this study we analyzed sex-differences in comprehension of texts in Spanish (standardized reading test PROLEC-R) in three modalities (visual, auditory, and both simultaneously: dual-modality) presented to 12-14-years old students, native in Spanish. We controlled relevant cognitive variables such as attention (d2), phonological and semantic fluency (FAS) and speed of processing (WISC subtest Coding). Girls' comprehension was similar in the three modalities of presentation, however boys were importantly benefited by dual-modality as compared to boys exposed only to visual or auditory text presentation. With respect to the relation of text comprehension and school performance, students with low grades in Spanish showed low auditory comprehension. Interestingly, visual and dual modalities preserved comprehension levels in these low skilled students. Our results suggest that the use of visual-text support during auditory language presentation could be beneficial for low school performance students, especially boys, and encourage future research to evaluate the implementation in classes of the rapidly developing technology of simultaneous speech transcription, that could be, in addition, beneficial to non-native students, especially those recently incorporated into school or newly arrived in a country from abroad.

Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.

Neuronal adaptation involves rapid expansion of the action potential initiation site.

Action potential (AP) generation is the key to information-processing in the brain. Although APs are normally initiated in the axonal initial segment, developmental adaptation or prolonged network activity may alter the initiation site geometry thus affecting cell excitability. Here we find that hippocampal dentate granule cells adapt their spiking threshold to the kinetics of the ongoing dendrosomatic excitatory input by expanding the AP-initiation area away from the soma while also decelerating local axonal spikes. Dual-patch soma-axon recordings combined with axonal Na(+) and Ca(2+) imaging and biophysical modelling show that the underlying mechanism involves distance-dependent inactivation of axonal Na(+) channels due to somatic depolarization propagating into the axon. Thus, the ensuing changes in the AP-initiation zone and local AP propagation could provide activity-dependent control of cell excitability and spiking on a relatively rapid timescale.

Focal adhesion kinase regulates actin nucleation and neuronal filopodia formation during axonal growth.

The establishment of neural circuits depends on the ability of axonal growth cones to sense their surrounding environment en route to their target. To achieve this, a coordinated rearrangement of cytoskeleton in response to extracellular cues is essential. Although previous studies have identified different chemotropic and adhesion molecules that influence axonal development, the molecular mechanism by which these signals control the cytoskeleton remains poorly understood. Here, we show that in vivo conditional ablation of the focal adhesion kinase gene (Fak) from mouse hippocampal pyramidal cells impairs axon outgrowth and growth cone morphology during development, which leads to functional defects in neuronal connectivity. Time-lapse recordings and in vitro FRAP analysis indicate that filopodia motility is altered in growth cones lacking FAK, probably owing to deficient actin turnover. We reveal the intracellular pathway that underlies this process and describe how phosphorylation of the actin nucleation-promoting factor N-WASP is required for FAK-dependent filopodia formation. Our study reveals a novel mechanism through which FAK controls filopodia formation and actin nucleation during axonal development.

Contribution of BK channels to action potential repolarisation at minimal cytosolic Ca2+ concentration in chromaffin cells.

BK channels modulate cell firing in excitable cells in a voltage-dependent manner regulated by fluctuations in free cytosolic Ca(2+) during action potentials. Indeed, Ca(2+)-independent BK channel activity has ordinarily been considered not relevant for the physiological behaviour of excitable cells. We employed the patch-clamp technique and selective BK channel blockers to record K(+) currents from bovine chromaffin cells at minimal intracellular (about 10 nM) and extracellular (free Ca(2+)) Ca(2+) concentrations. Despite their low open probability under these conditions (V(50) of +146.8 mV), BK channels were responsible for more than 25% of the total K(+) efflux during the first millisecond of a step depolarisation to +20 mV. Moreover, BK channels activated about 30% faster (τ = 0.55 ms) than the rest of available K(+) channels. The other main source of fast voltage-dependent K(+) efflux at such a low Ca(2+) was a transient K(+) (I(A)-type) current activating with V (50) = -14.2 mV. We also studied the activation of BK currents in response to action potential waveforms and their contribution to shaping action potentials both in the presence and the absence of extracellular Ca(2+). Our results show that BK channels activate during action potentials and accelerate cell repolarisation even at minimal Ca(2+) concentration, and suggest that they could do so also in the presence of extracellular Ca(2+), before Ca(2+) entering the cell facilitates their activity.

Slow GABA transient and receptor desensitization shape synaptic responses evoked by hippocampal neurogliaform cells.

The kinetics of GABAergic synaptic currents can vary by an order of magnitude depending on the cell type. The neurogliaform cell (NGFC) has recently been identified as a key generator of slow GABA(A) receptor-mediated volume transmission in the isocortex. However, the mechanisms underlying slow GABA(A) receptor-mediated IPSCs and their use-dependent plasticity remain unknown. Here, we provide experimental and modeling data showing that hippocampal NGFCs generate an unusually prolonged (tens of milliseconds) but low-concentration (micromolar range) GABA transient, which is responsible for the slow response kinetics and which leads to a robust desensitization of postsynaptic GABA(A) receptors. This strongly contributes to the use-dependent synaptic depression elicited by various patterns of NGFC activity including the one detected during theta network oscillations in vivo. Synaptic depression mediated by NGFCs is likely to play an important modulatory role in the feedforward inhibition of CA1 pyramidal cells provided by the entorhinal cortex.

Presynaptic GABAA receptors enhance transmission and LTP induction at hippocampal mossy fiber synapses.

Presynaptic GABA(A) receptors (GABA(A)Rs) occur at hippocampal mossy fiber synapses. Whether and how they modulate orthodromic signaling to postsynaptic targets is poorly understood. We found that an endogenous neurosteroid that is selective for high-affinity delta subunit-containing GABA(A)Rs depolarized rat mossy fiber boutons, enhanced action potential-dependent Ca(2+) transients and facilitated glutamatergic transmission to pyramidal neurons. Conversely, blocking GABA(A)Rs hyperpolarized mossy fiber boutons, increased their input resistance, decreased spike width and attenuated action potential-dependent presynaptic Ca(2+) transients, indicating that a subset of presynaptic GABA receptors are tonically active. Blocking GABA(A)Rs also interfered with the induction of long-term potentiation at mossy fiber-CA3 synapses. Presynaptic GABA(A)Rs therefore facilitate information flow to the hippocampus both directly and by enhancing LTP.

Target-cell specificity of kainate autoreceptor and Ca2+-store-dependent short-term plasticity at hippocampal mossy fiber synapses.

Presynaptic kainate receptors (KARs) modulate transmission between dentate granule cells and CA3 pyramidal neurons. Whether presynaptic KARs affect other synapses made by granule cell axons [mossy fibers (MFs)], on hilar mossy cells or interneurons, is not known. Nor is it known whether glutamate release from a single MF is sufficient to activate these receptors. Here, we monitor Ca(2+) in identified MF boutons traced from granule cell bodies. We show that a single action potential in a single MF activates both presynaptic KARs and Ca(2+) stores, contributing to use-dependent facilitation at MF-CA3 pyramidal cell synapses. Rapid local application of kainate to the giant MF bouton has no detectable effect on the resting Ca(2+) but facilitates action-potential-evoked Ca(2+) entry through a Ca(2+) store-dependent mechanism. Localized two-photon uncaging of the Ca(2+) store receptor ligand IP(3) directly confirms the presence of functional Ca(2+) stores at these boutons. In contrast, presynaptic Ca(2+) kinetics at MF synapses on interneurons or mossy cells are insensitive to KAR blockade, to local kainate application or to photolytic release of IP(3). Consistent with this, postsynaptic responses evoked by activation of a single MF show KAR-dependent paired-pulse facilitation in CA3 pyramidal cells, but not in interneurons or mossy cells. Thus, KAR-Ca(2+) store coupling acts as a synapse-specific, short-range autoreceptor mechanism.

Analog modulation of mossy fiber transmission is uncoupled from changes in presynaptic Ca2+.

Subthreshold somatic depolarization has been shown recently to modulate presynaptic neurotransmitter release in cortical neurons. To understand the mechanisms underlying this mode of signaling in the axons of dentate granule cells (hippocampal mossy fibers), we have combined two-photon Ca2+ imaging with dual-patch recordings from somata and giant boutons forming synapses on CA3 pyramidal cells. In intact axons, subthreshold depolarization propagates both orthodromically and antidromically, with an estimated length constant of 200-600 microm depending on the signal waveform. Surprisingly, presynaptic depolarization sufficient to enhance glutamate release at mossy fiber-CA3 pyramidal cell synapses has no detectable effect on either basal Ca2+-dependent fluorescence or action-potential-evoked fluorescence transients in giant boutons. We further estimate that neurotransmitter release varies with presynaptic Ca2+ entry with a 2.5-power relationship and that depolarization-induced synaptic facilitation remains intact in the presence of high-affinity presynaptic Ca2+ buffers or after blockade of local Ca2+ stores. We conclude that depolarization-dependent modulation of transmission at these boutons does not rely on changes in presynaptic Ca2+.

GABA(B) receptor modulation of feedforward inhibition through hippocampal neurogliaform cells.

Feedforward inhibition of neurons is a fundamental component of information flow control in the brain. We studied the roles played by neurogliaform cells (NGFCs) of stratum lacunosum moleculare of the hippocampus in providing feedforward inhibition to CA1 pyramidal cells. We recorded from synaptically coupled pairs of anatomically identified NGFCs and CA1 pyramidal cells and found that, strikingly, a single presynaptic action potential evoked a biphasic unitary IPSC (uIPSC), consisting of two distinct components mediated by GABA(A) and GABA(B) receptors. A GABA(B) receptor-mediated unitary response has not previously been observed in hippocampal excitatory neurons. The decay of the GABA(A) receptor-mediated response was slow (time constant = 50 ms), and was tightly regulated by presynaptic GABA(B) receptors. Surprisingly, the GABA(B) receptor ligands baclofen and (2S)-3-{[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl}(phenylmethyl)phosphinic acid (CGP55845), while affecting the NGFC-mediated uIPSCs, had no effect on action potential-evoked presynaptic Ca2+ signals monitored in individual axonal boutons of NGFCs with two-photon microscopy. In contrast, baclofen clearly depressed presynaptic Ca2+ transients in non-NGF interneurons. Changes in extracellular Ca2+ concentration that mimicked the effects of baclofen or CGP55845 on uIPSCs significantly altered presynaptic Ca2+ transients. Electrophysiological data suggest that GABA(B) receptors expressed by NGFCs contribute to the dynamic control of the excitatory input to CA1 pyramidal neurons from the temporoammonic path. The NGFC-CA1 pyramidal cell connection therefore provides a unique and subtle mechanism to shape the integration time domain for signals arriving via a major excitatory input to CA1 pyramidal cells.

Use-dependent control of presynaptic calcium signalling at central synapses.

Voltage-gated Ca(2+) channels activated by action potentials evoke Ca(2+) entry into presynaptic terminals thus briefly distorting the resting Ca(2+) concentration. When this happens, a number of processes are initiated to re-establish the Ca(2+) equilibrium. During the post-spike period, the increased Ca(2+) concentration could enhance the presynaptic Ca(2+) signalling. Some of the mechanisms contributing to presynaptic Ca(2+) dynamics involve endogenous Ca(2+) buffers, Ca(2+) stores, mitochondria, the sodium-calcium exchanger, extraterminal Ca(2+) depletion and presynaptic receptors. Additionally, subthreshold presynaptic depolarization has been proposed to have an effect on release of neurotransmitters through a mechanism involving changes in resting Ca(2+). Direct evidence for the role of any of these participants in shaping the presynaptic Ca(2+) dynamics comes from direct recordings of giant presynaptic terminals and from fluorescent Ca(2+) imaging of axonal boutons. Here, some of this evidence is presented and discussed.

Main determinants of presynaptic Ca2+ dynamics at individual mossy fiber-CA3 pyramidal cell synapses.

Synaptic transmission between hippocampal mossy fibers (MFs) and CA3 pyramidal cells exhibits remarkable use-dependent plasticity. The underlying presynaptic mechanisms, however, remain poorly understood. Here, we have used fluorescent Ca2+ indicators Fluo-4, Fluo-5F, and Oregon Green BAPTA-1 to investigate Ca2+ dynamics in individual giant MF boutons (MFBs) in area CA3 traced from the somata of granule cells held in whole-cell mode. In an individual MFB, a single action potential induces a brief peak of free Ca2+ (estimated in the range of 8-9 microm) followed by an elevation to approximately 320 nm, which slowly decays to its resting level of approximately 110 nm. Changes in the somatic membrane potential influence presynaptic Ca2+ entry at proximal MFBs in the hilus. This influence decays with distance along the axon, with a length constant of approximately 200 microm. In giant MFBs in CA3, progressive saturation of endogenous Ca2+ buffers during repetitive spiking amplifies rapid Ca2+ peaks and the residual Ca2+ severalfold, suggesting a causal link to synaptic facilitation. We find that internal Ca2+ stores contribute to maintaining the low resting Ca2+ providing approximately 22% of the buffering/extrusion capacity of giant MFBs. Rapid Ca2+ release from stores represents up to 20% of the presynaptic Ca2+ transient evoked by a brief train of action potentials. The results identify the main components of presynaptic Ca2+ dynamics at this important cortical synapse.

Presynaptic, extrasynaptic and axonal GABAA receptors in the CNS: where and why?

Although GABA(A) receptors are widely distributed at inhibitory synapses on dendrites and cell bodies of neurons, they also occur in other places, in particular at synapses made on axons and in extrasynaptic membranes. This review summarises some of the evidence that presynaptic receptors modulate transmission not only at primary afferents in the spinal cord, but also at a variety of sites in the brain, including hippocampal mossy fibres. These receptors modulate transmitter release via several different mechanisms. Another form of unconventional GABA(A) receptor-mediated signalling is the mediation of a tonic conductance, seen in granule cells of the cerebellum and dentate gyrus and also in hippocampal interneurons. Tonic signalling appears to be mediated by extrasynaptic receptors. The adaptive significance of this form of signalling remains poorly understood.

GABAA receptors at hippocampal mossy fibers.

Presynaptic GABAA receptors modulate synaptic transmission in several areas of the CNS but are not known to have this action in the cerebral cortex. We report that GABAA receptor activation reduces hippocampal mossy fibers excitability but has the opposite effect when intracellular Cl- is experimentally elevated. Synaptically released GABA mimics the effect of exogenous agonists. GABAA receptors modulating axonal excitability are tonically active in the absence of evoked GABA release or exogenous agonist application. Presynaptic action potential-dependent Ca2+ transients in individual mossy fiber varicosities exhibit a biphasic dependence on membrane potential and are altered by GABAA receptors. Antibodies against the alpha2 subunit of GABAA receptors stain mossy fibers. Axonal GABAA receptors thus play a potentially important role in tonic and activity-dependent heterosynaptic modulation of information flow to the hippocampus.