The segregation of sensory information into distinct cortical areas is an important organizational feature of mammalian sensory systems. Here, we provide functional magnetic resonance imaging (fMRI) evidence for the functional delineation of somatosensory representations in the human central sulcus region. Data were collected with a 3-Tesla scanner during two stimulation protocols, a punctate tactile condition without a kinesthetic/motor component, and a kinesthetic/motor condition without a punctate tactile component. With three-dimensional (3-D) anatomical reconstruction techniques, we analyzed data in individual subjects, using the pattern of activation and the anatomical position of specific cortical areas to guide the analysis. As a complimentary analysis, we used a brain averaging technique that emphasized the similarity of cortical features in the morphing of individual subjects and thereby minimized the distortion of the location of cortical activation sites across individuals. A primary finding of this study was differential activation of the cortex on the fundus of the central sulcus, the position of area 3a, during the two tasks. Punctate tactile stimulation of the palm, administered at 3 Hz with a 5.88(log10.mg) von Frey filament, activated discrete regions within the precentral (PreCG) and postcentral (PoCG) gyri, corresponding to areas 6, 3b, 1, and 2, but did not activate area 3a. Conversely, kinesthetic/motor stimulation, 3-Hz flexion and extension of the digits, activated area 3a, the PreCG (areas 6 and 4), and the PoCG (areas 3b, 1, and 2). These activation patterns were observed in individual subjects and in the averaged data, providing strong evidence for the existence of a distinct representation within area 3a in humans. The percentage signal changes in the PreCG and PoCG regions activated by tactile stimulation, and in the intervening gap region, support this functional dissociation. In addition to this distinction within the fundus of the central sulcus, the combination of high-resolution imaging and 3-D analysis techniques permitted localization of activation within areas 6, 4, 3a, 3b, 1, and 2 in the human. With the exception of area 4, which showed inconsistent activation during punctate tactile stimulation, activation in these areas in the human consistently paralleled the pattern of activity observed in previous studies of monkey cortex.
Alternative splicing is a critical mechanism used extensively in the mammalian nervous system to increase the level of diversity that can be achieved by a set of genes. This review focuses on recent studies of voltage-gated calcium (Ca) channel Ca(v)alpha1 subunit splice isoforms in neurons. Voltage-gated Ca channels couple changes in neuronal activity to rapid changes in intracellular Ca levels that in turn regulate an astounding range of cellular processes. Only ten genes have been identified that encode Ca(v)alpha1 subunits, an insufficient number to account for the level of functional diversity among voltage-gated Ca channels. The consequences of regulated alternative splicing among the genes that comprise voltage-gated Ca channels permits specialization of channel function, optimizing Ca signaling in different regions of the brain and in different cellular compartments. Although the full extent of alternative splicing is not yet known for any of the major subtypes of voltage-gated Ca channels, it is already clear that it adds a rich layer of structural and functional diversity".
Calcium ion channels coordinate an astounding number of cellular functions. Surprisingly, only 10 Ca(V)alpha(1) subunit genes encode the structural cores of all voltage-gated calcium channels. What mechanisms exist to modify the structure of calcium channels and optimize their coupling to the rich spectrum of cellular functions? Growing evidence points to the contribution of post-translational alternative processing of calcium channel RNA as the main mechanism for expanding the functional potential of this important gene family. Alternative splicing of RNA is essential during neuronal development where fine adjustments in protein signaling promote and inhibit cell-cell interactions and underlie axonal guidance. However, attributing a specific functional role to an individual splice isoform or splice site has been difficult. In this regard, studies of ion channels are advantageous because their function can be monitored with precision, allowing even subtle changes in channel activity to be detected. Such studies are especially insightful when coupled with information about isoform expression patterns and cellular localization. In this paper, we focus on two sites of alternative splicing in the N-type calcium channel Ca(V)2.2 gene. We first describe cassette exon 18a that encodes a 21 amino acid segment in the II-III intracellular loop region of Ca(V)2.2. Here, we show that e18a is upregulated in the nervous system during development. We discuss these new data in light of our previous reports showing that e18a protects the N-type channel from cumulative inactivation. Second, we discuss our published data on exons e37a and e37b, which encode 32 amino acids in the intracellular C-terminus of Ca(V)2.2. These exons are expressed in a mutually exclusive manner. Exon e37a-containing Ca(V)2.2 mRNAs and their resultant channels express at higher density in dorsal root ganglia and, as we showed recently, e37a increases N-type channel sensitivity to G-protein-mediated inhibition, as compared to generic e37b-containing N-type channels.
The CaV2 family of voltage-gated calcium channels, present in presynaptic nerve terminals, regulates exocytosis and synaptic transmission. Cumulative inactivation of these channels occurs during trains of action potentials, and this may control short-term dynamics at the synapse. Inactivation during brief, repetitive stimulation is primarily attributed to closed-state inactivation, and several factors modulate the susceptibility of voltage-gated calcium channels to this form of inactivation. We show that alternative splicing of an exon in a cytoplasmic region of the Ca V2.2 channel modulates its sensitivity to inactivation during trains of action potential waveforms. The presence of this exon, exon 18a, protects the Ca V 2.2 channel from entry into closed-state inactivation specifically during short (10 ms to 3 s) and small depolarizations of the membrane potential (؊60 mV to ؊50 mV). The reduced sensitivity to closed-state inactivation within this dynamic range likely underlies the differential responsiveness of Ca V2.2 splice isoforms to trains of action potential waveforms. Regulated alternative splicing of Ca V2.2 represents a possible mechanism for modulating short-term dynamics of synaptic efficacy in different regions of the nervous system. T he Ca V 2 class of voltage-gated calcium channels regulates calcium entry that triggers exocytosis from presynaptic nerve terminals (1). The temporal dynamics of calcium channel responses to action potential trains impact the fidelity of synaptic transmission (2). Membrane depolarization both activates and inactivates voltage-gated calcium channels. With repetitive, brief depolarizations, inactivation of calcium channels accumulates over time and progressively decreases calcium entry.Cumulative inactivation, a feature of both native and cloned Ca V 2 calcium channels, has been studied in detail because of its importance in regulating the short-term dynamics of synaptic efficacy (2-8). Inactivation that accumulates during brief, repetitive stimulation is thought to result from a process known as closed-state inactivation (5, 6). That is, voltage-gated calcium channels undergo inactivation in response to depolarizations that are insufficiently large to open the channel. Open-state inactivation is thought to play only a minor role in cumulative inactivation of Ca V 2 calcium channels during brief stimuli such as action potentials. Even during prolonged depolarizations that favor open-state inactivation, Ca V 2 channels inactivate with relatively slow time courses. Only in the case of Ca V 3 channels that deactivate relatively slowly following action potential repolarization has open-state inactivation been implicated in cumulative inactivation (9-11). Several factors modulate the susceptibility of voltage-gated calcium channels to cumulative inactivation, including channel subtype (6), G protein activation (3), interaction with presynaptic proteins (12, 13), and alternative splicing (10, 11). However, a limited number of studies have investigated the mechanisms by which...
Sensory microcircuits are refined by experience during windows of heightened plasticity termed "critical periods" (CPs). In visual cortex the effects of visual deprivation change dramatically at the transition from the pre-CP to the CP, but the cellular plasticity mechanisms that underlie this change are poorly understood. Here we show that plasticity at unitary connections between GABAergic Fast Spiking (FS) cells and Star Pyramidal (SP) neurons within layer 4 flips sign at the transition between the pre-CP and the CP. During the pre-CP, coupling FS firing with SP depolarization induces longterm depression of inhibition at this synapse, whereas the same protocol induces long-term potentiation of inhibition at the opening of the CP. Despite being of opposite sign, both forms of plasticity share expression characteristics-a change in coefficient of variation with no change in paired-pulse ratio-and depend on GABA B receptor signaling. Finally, we show that the reciprocal SP→FS synapse also acquires the ability to undergo long-term potentiation at the pre-CP to CP transition. Thus, at the opening of the CP, there are coordinated changes in plasticity that allow specific patterns of activity within layer 4 to potentiate feedback inhibition by boosting the strength of FS↔SP connections.S ensory microcircuits are refined by experience during windows of heightened plasticity termed "critical periods" (CPs). In visual cortex the classical CP was defined based on when visual deprivation (VD) induces ocular dominance (OD) shifts, between approximately postnatal days (P) 20-33 (1-3). However, visual cortex is also plastic during a pre-CP between eye opening (∼P14) and the onset of the classical CP (4-6). Although both developmental windows are characterized by sensitivity to visual experience, the effects of VD change dramatically at the transition between these two developmental stages (7-10).The cellular changes that underlie the transition from pre-CP to CP plasticity remain incompletely understood, but recent work has implicated a specific inhibitory network involving parvalbumin-positive fast-spiking (FS) basket cells in this process (8,11,12). FS cells provide strong somatic inhibition onto cortical pyramidal neurons, and this inhibition matures significantly between eye opening and the opening of the classical CP (13-15). Further, reducing or enhancing this inhibition can prevent or prematurely trigger the transition from pre-CP to CP plasticity (11,(16)(17)(18). Thus, maturation of FS inhibition is thought to be causally involved in triggering CP plasticity, but exactly what aspect of this maturation drives these changes is unknown. One characteristic of this maturation is a change in the response of FS synapses to VD. Brief monocular VD during the pre-CP decreases inhibitory synaptic strength from FS to star pyramidal (SP) neurons in layer 4 (L4) of the monocular primary visual cortex [V1m (19)] but increases inhibition at the same synapse when performed during the CP (20). There is evidence that longterm potenti...
Fragile X Syndrome is the most prevalent genetic cause of mental retardation. Selective deficits in executive function, including inhibitory control and attention, are core features of the disorder. In humans, Fragile X results from a trinucleotide repeat in the Fmr1 gene that renders it functionally silent and has been modeled in mice by targeted deletion of the Fmr1 gene. Fmr1 knockout (KO) mice recapitulate many features of Fragile X syndrome, but evidence for deficits in executive function is inconsistent. To address this issue, we trained wild-type and Fmr1 KO mice on an experimental paradigm that assesses attentional set-shifting. Mice learned to discriminate between stimuli differing in two of three perceptual dimensions. Successful discrimination required attending only to the relevant dimension, while ignoring irrelevant dimensions. Mice were trained on three discriminations in the same perceptual dimension, each followed by a reversal. This procedure normally results in the formation of an attentional set to the relevant dimension. Mice were then required to shift attention and discriminate based on a previously irrelevant perceptual dimension. Wild-type mice exhibited the increase in trials to criterion expected when shifting attention from one perceptual dimension to another. In contrast, the Fmr1 KO group failed to show the expected increase, suggesting impairment in forming an attentional set. Fmr1 KO mice also exhibited a general impairment in learning discriminations and reversals. This is the first demonstration that Fmr1 KO mice show a deficit in attentional set formation.
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