1,720,987 research outputs found
Presynaptic current changes at the mossy fiber - granule cell synapse of cerebellum during LTP
Full text linkThe involvement of presynaptic mechanisms in the expression of long-term potentiation (LTP), an enhancement of synaptic transmission suggested to take part in learning and memory in the mammalian brain, has not been fully clarified. Although evidence for enhanced vesicle cycling has been reported, it is unknown whether presynaptic terminal excitability could change as has been observed in invertebrate synapses. To address this question, we performed extracellular focal recordings in cerebellar slices. The extracellular current consisted of a pre- (P(1)/N(1)) and postsynaptic (N(2)/SN) component. In ~50% of cases, N(1) could be subdivided into N(1a) and N(1b). Whereas N(1a) was part of the fiber volley (P(1)/N(1a)), N(1b) corresponded to a Ca(2+)-dependent component accounting for 40-50% of N(1), which could be isolated from individual mossy fiber terminals visualized with fast tetramethylindocarbocyanine perchlorate (DiI). The postsynaptic response, given its timing and sensitivity to glutamate receptor antagonists [N(2) was blocked by 10 microM [1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodium (NBQX) and SN by 100 microM APV +50 microM 7-Cl-kyn], corresponded to granule cell excitation. N(2) and SN could be reduced by 1) Ca(2+) channel blockers, 2) decreasing the Ca(2+) to Mg(2+) ratio, 3) paired-pulse stimulation, and 4) adenosine receptor activation. However, only the first two manipulations, which modify Ca(2+) influx, were associated with N(1) (or N(1b)) reduction. LTP was induced by theta-burst mossy fiber stimulation (8 trains of 10 impulses at 100 Hz separated by 150-ms pauses). Interestingly, during LTP, both N(1) (or N(1b)) and N(2)/SN persistently increased, whereas P(1) (or P(1)/N(1a)) did not change. Average changes were N(1) = 38.1 +/- 31.9, N(2) = 49.6 +/- 48.8, and SN = 59.1 +/- 35.5%. The presynaptic changes were not observed when LTP was prevented by synaptic inhibition, by N-methyl-D-aspartate and metabotropic glutamate receptor blockage, or by protein kinase C blockage. Moreover, the presynaptic changes were sensitive to Ca(2+) channel blockers (1 mM Ni(2+) and 5 microM omega-CTx-MVIIC) and occluded by K(+) channel blockers (1 mM tetraethylammmonium). Thus regulation of presynaptic terminal excitability may take part in LTP expression at a central mammalian synapse
Differential induction of bidirectional long-term changes in neurotransmitter release by frequency-coded patterns at the cerebellar input
No full textSensory stimulation conveys spike discharges of variable frequency and duration along the mossy fibres of cerebellum raising the question of whether and how these patterns determine plastic changes at the mossy fibre-granule cell synapse. Although various combinations of high-frequency bursts and membrane depolarization can induce NMDA receptor-dependent long-term depression (LTD) and long-term potentiation (LTP), the effect of different discharge frequencies remained unknown. Here we show that low-frequency mossy fibre stimulation (100 impulses-1 Hz) induces mGlu receptor-dependent LTD. For various burst frequencies, the plasticity-[Ca2+](i) relationship was U-shaped resembling the Bienenstok-Cooper-Munro (BCM) learning rule. Moreover, LTD expression was associated with increased paired-pulse ratio, coefficient of variation and failure rate, and with a decrease in release probability, therefore showing changes opposite to those characterizing LTP. The plasticity-[Ca2+](i) relationship and the changes in neurotransmitter release measured by varying induction frequencies were indistinguishable from those obtained by varying high-frequency burst duration. These results suggest that different glutamate receptors converge onto a final common mechanism translating the frequency and duration of mossy fibre discharges into a regulation of the LTP/LTD balance, which may play an important role in adapting spatio-temporal signal transformations at the cerebellar input stag
Understanding Cerebellar Input Stage through Computational and Plasticity Rules
No full textA central hypothesis concerning brain functioning is that plasticity regulates the signal transfer function by modifying the efficacy of synaptic transmission. In the cerebellum, the granular layer has been shown to control the gain of signals transmitted through the mossy fiber pathway. Until now, the impact of plasticity on incoming activity patterns has been analyzed by combining electrophysiological recordings in acute cerebellar slices and computational modeling, unraveling a broad spectrum of different forms of synaptic plasticity in the granular layer, often accompanied by forms of intrinsic excitability changes. Here, we attempt to provide a brief overview of the most prominent forms of plasticity at the excitatory synapses formed by mossy fibers onto primary neuronal components (granule cells, Golgi cells and unipolar brush cells) in the granular layer. Specifically, we highlight the current understanding of the mechanisms and their functional implications for synaptic and intrinsic plasticity, providing valuable insights into how inputs are processed and reconfigured at the cerebellar input stage
The Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models
No full textAutism spectrum disorders (ASD) are pervasive neurodevelopmental disorders that include a variety of forms and clinical phenotypes. This heterogeneity complicates the clinical and experimental approaches to ASD etiology and pathophysiology. To date, a unifying theory of these diseases is still missing. Nevertheless, the intense work of researchers and clinicians in the last decades has identified some ASD hallmarks and the primary brain areas involved. Not surprisingly, the areas that are part of the so-called "social brain", and those strictly connected to them, were found to be crucial, such as the prefrontal cortex, amygdala, hippocampus, limbic system, and dopaminergic pathways. With the recent acknowledgment of the cerebellar contribution to cognitive functions and the social brain, its involvement in ASD has become unmistakable, though its extent is still to be elucidated. In most cases, significant advances were made possible by recent technological developments in structural/functional assessment of the human brain and by using mouse models of ASD. Mouse models are an invaluable tool to get insights into the molecular and cellular counterparts of the disease, acting on the specific genetic background generating ASD-like phenotype. Given the multifaceted nature of ASD and related studies, it is often difficult to navigate the literature and limit the huge content to specific questions. This review fulfills the need for an organized, clear, and state-of-the-art perspective on cerebellar involvement in ASD, from its connections to the social brain areas (which are the primary sites of ASD impairments) to the use of monogenic mouse models
Post-synaptic regulation in unipolar brush cell by voltage-dependent currents
No full textCerebellar granular layer contains, in addition to granule and Golgi cells, the unipolar brush cells (UBCs). Although several works revealing the basic synaptic and excitable properties of UBCs (Rossi et al., 1995; Diana et al., 2007), synaptic activation mechanisms remained poorly understood. By using patch-clamp recordings in rat vestibulo-cerebellar slices (P17-P24; n=160), we found that mossy fiber (MF) stimulation also evoked (~70% of cases) a late-onset burst (tens to hundreds of milliseconds) independent from previous EPSP generation. This burst delay decreased, its duration increased by raising MF stimulation intensity and was initiated by a slow depolarizing ramp, driven by activation of a ZD7288-and Cs+-sensitive H-current (Ih). The effect was reinforced by a cooperative contribution from TRP channels and was occluded by cAMP. After perfusion of 2 μM ZD 7288, the slope of the depolarizing ramp leading to the late-onset burst decreased resulting in a significant increase of the burst delay (65,32%± 41,92%; p<0.1). The increase of inward currents by MF stimulation was significantly reduced by intracellular perfusion of 500 μM cAMP through the patch pipette: from 29.3±5.3% to 8.6±3.3% at the end of current step; p<0.01. These results indicate that MF activity can regulate Ih gating through a yet unknown neuromodulator mechanism. This novel modality of UBC activation may play an important role for regulating granular layer functions in the vestibulo-cerebellum
Autism and genius : is there a link? The involvement of central brain loops and hypotheses for functional testing
Full text linkMental processing is the product of the huge number of synaptic interactions that occur in the brain. It is easier to understand how brain functions can deteriorate than how they might be boosted. Lying at the border between the humanities, cognitive science and neurophysiology, some mental diseases offer new angles on this problematic issue. Despite their social deficits, autistic subjects can display unexpected and extraordinary skills in numerous fields, including music, the arts, calculation and memory. The advanced skills found in a subgroup of people with autism may be explained by their special mental functioning, in particular by their weak central coherence, one of the pivotal characteristics of the disorder. As a result of the increasing interest in autistic talent, there has recently emerged a tendency to screen any eccentric artist or scientist for traits of the autistic spectrum. Following this trend, we analyze the eccentricity of the popular pianist Glenn Gould and briefly discuss the major functional hypotheses on autistic hyperfunctioning, advancing proposals for functional testing. In particular, the potential involvement of rhythm-entrained systems and cerebro-cerebellar loops opens up new perspectives for the investigation of autistic disorders and
brain hyperfunctioning
Evidence for long-term synaptic plasticity at the mossy fiber - Golgi cell synapse of cerebellum
No full textProgramme and Abstracts of the 66th National Congress of the Italian Physiological Society (Società Italiana di Fisiologia
Increased neurotransmitter release during long-term potentiation at mossy fibre-granule cell synapses in rat cerebellum
No full textDuring long-term potentiation (LTP) at mossy fibre-granule cell synapses in rat cerebellum synaptic transmission and granule cell intrinsic excitability are enhanced. Although it is clear that changes in granule cell excitability are mediated postsynaptically, there is as yet no direct evidence for the site and mechanism of changes in transmission. To approach this problem, evoked postsynaptic currents (EPSCs) and miniature synaptic currents (mEPSCs) were recorded by patch-clamp in cerebellar slices obtained from P17-P23 rats. LTP was induced by theta-burst stimulation paired with depolarization. During LTP, the EPSCs showed a significant decrease in the coefficient of variation (CV; 28.9 +/- 5.2%, n= 8; P < 0.002), the number of failures (87.1 +/- 41.9%, n= 8; P < 0.04), and the paired-pulse ratio (PPR; 25.5 +/- 4.1% n= 5; P < 0.02). Similar changes were observed by increasing neurotransmitter release (extracellular solutions with high Ca(2+)/Mg(2+) ratio), whereas increases in CV, numbers of failures and PPR occurred when release was decreased (extracellular solutions with low Ca(2+)/Mg(2+) ratio; 10 microm Cl-adenosine). No changes followed modifications of postsynaptic holding potentials, while CV and failures were reduced when the number of active synapses was increased. LTP was prevented by use of solutions with high Ca(2+)/Mg(2+) ratio. Moreover, LTP and the associated CV decrease were observed in the spillover-mediated component of AMPA EPSCs and in NMDA EPSCs. During LTP, mEPSCs did not change in amplitude or variability but significantly increased in frequency (47.6 +/- 16%, n= 4; P < 0.03). By binomial analysis changes in EPSCs were shown to be due to increased release probability (from 0.6 +/- 0.08 to 0.73 +/- 0.06, n= 7; P < 0.02) with a constant number of three to four releasing sites. These observations provide evidence for increased neurotransmitter release during LTP at mossy fibre-granule cell synapses
Cerebellar hyper-plasticity in the IB2 KO mouse model of autism
No full textAutism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders that include syndromes with familial conditions. Among these, the Phelan-McDermid syndrome is associated with the co-deletion of SHANK3 and IB2 genes at the chromosome 22q terminus. Although much attention has been devoted to characterize SHANK3 mutations, very little is known about the role of IB2 in ASDs. The IB2 protein is expressed at synapses and takes part to the NMDA receptor (NMDAR) interactome in the postsynaptic densities. Experimental disruption of the IB2 gene in transgenic mice determined an enhanced NMDAR-mediated transmission at the mossy fiber-granule cell (MF-GrCs) synapse in the cerebellum. Moreover, IB2 knocked-out (IB2 KO) mice showed motor and cognitive deficits, making them a reliable ASD model [1]. Herein, we further investigated the synaptic and circuit modifications in IB2 KO mice. In particular, we addressed the potential alterations in the excitatory/inhibitory (E/I) balance and long-term potentiation (LTP) induction in the cerebellar granular layer of IB2 KO mice
Late-onset bursts evoked by mossy fiber bundle stimulation in unipolar brush cells: evidence for the involvement of H- and TRP-currents
Full text linkSynaptic transmission at central synapses has usually short latency and graded amplitude, thereby regulating threshold crossing and the probability of action potential generation. In the granular layer of vestibulo-cerebellum, the unipolar brush cells (UBCs) receive a giant synapse generating a stereotyped EPSP-burst complex with early-onset (~ 2 ms) and high reliability. By using patch-clamp recordings in cerebellar slices of the rat vestibulo-cerebellum, we found that mossy fiber bundle stimulation also evoked (in ~80% of cases) a late-onset burst (after tens to hundreds milliseconds) independent from EPSP generation. Different from the early-onset, the late-onset burst delay decreased and its duration increased by raising stimulation intensity or the number of impulses. Though depending on synaptic activity, the late-onset response was insensitive to APV, NBQX and MCPG perfusion and did not therefore depend on conventional glutamatergic transmission mechanisms. The late-onset response was initiated by a slow depolarizing ramp driven by activation of an H-current (sensitive to ZD7288- and Cs+) and of a TRP-current (sensitive to SKF96365), while the HVA and LVA Ca2+-currents (sensitive to nimodipine and mibefradil) played a negligible role. The late-onset burst was occluded by intracellular cAMP. These results indicate that afferent activity can regulate H- and TRP-current gating in UBCs generating synaptically-driven EPSP-independent responses, in which the delay rather than amplitude is graded with the intensity of the input pattern. This modality of synaptic transmission may play an important role for regulating UBC activation and granular layer functions in the vestibulo-cerebellu
- …
