Multiple Erythroid Ankyrin Isoforms in the Mouse Cerebellum: Differential Localization in Purkinje Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1725-1725
Author(s):  
Connie B. Birkenmeier ◽  
Timothy H. Young ◽  
Jane E. Barker ◽  
Luanne L. Peters
Keyword(s):  
Axonal Transport ◽  
Purkinje Cells ◽  
Granule Cell ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Granule Cell Layer ◽  
Specific Marker ◽  
Functional Link ◽  
Mouse Cerebellum ◽  
And Function

Abstract The erythroid ankyrin gene (Ank1) produces a large and varied number of isoforms due to alternative splicing of the mRNA. In addition to expression in erythroid tissues, some of these Ank1 proteins are highly expressed in the Purkinje cells (PKC) of the mouse cerebellum. Mice deficient in Ank1 as a result of a mutation in the Ank1 gene (normoblastosis, nb) show a progressive loss of PKCs with an attendant ataxia. We have generated a panel of Ank1 antibodies to aid in sorting out the expression pattern and function of Ank1 proteins in the cerebellum. Two of these antibodies are specific to the alternatively spliced A and B COOH-terminal segments of Ank1. Immunohistochemical (IHC) experiments using these antibodies show strikingly different patterns of localization. Anti-C-termA (α-A) stains the PKC cell body and dendrites while anti-C-termB (α-B) is restricted to the PKC membrane. Both antibodies stain structures in the granule cell layer (GCL) including the granule cell membrane (α-B) and structures known as glomeruli where granule cell dendrites synapse with mossy fiber axons (α-A and α-B). Mossy fibers are a major afferent system that inputs to the cerebellum. α-A, α-B, antibodies to the α-1 subunit of Na+/K+ATPase (NaK-α1) and anti-Synapsin 1, a specific marker for synaptic vesicles, all co-localize in the glomeruli, suggesting a possible functional link. PKC membrane staining with α-B is absent in nb/nb cerebellum whereas PKC staining with α-A is unaffected. GCL staining with both antibodies is reduced in the mutant and this deficit may be important to PKC survival since granule cell axons are a major input system to PKC dendrites. Immunoblots stained with α-A and α-B are consistent with the IHC findings. In addition to the typical large isoforms (∼210kD) that are deficient in the nb mutant, immunoblots of cerebellar lysates reveal a number of small Ank1 related proteins ranging in size from 17 to 50 kD. The α-A and α-B banding patterns are unaffected by the nb mutation suggesting that they may be produced by splicing out the exon containing the nb mutation (E36) or by using an alternative promoter in the 3′ end of the gene as was found for the small Ank1 isoforms in skeletal muscle. Additional IHC findings using GFP-tagged PKC show a PKC axonopathy in nb/nb cerebellum. PKC axons exhibit multiple swellings that accumulate with age raising the possibility that axonal transport is abnormal in the nb PKCs. In summary 1) immunoblots reveal multiple previously undescribed small Ank1 isoforms in cerebellum, 2) two of the alternate Ank1 COOH-termini show very different localization in PKC suggesting distinct functions for the Ank1 proteins carrying them, 3) in the GCL, antibodies to the two COOH-termini co-localize with antibodies to the Na+/K+ATPase α-1 subunit in synaptic densities, 4) deficiencies of Ank1 in the GCL of nb/nb mice may influence PKC survival and 5) axonal transport may be affected in nb/nb PKC. These findings indicate that Ank1 proteins play a more varied role in the cerebellum than previously suspected and suggest new directions for the study of Ank1 function.

Optical Recording Study of Granule Cell Activities in the Hippocampal Dentate Gyrus of Kainate-Treated Rats

2000 ◽  
Vol 83 (4) ◽  
pp. 2421-2430 ◽  
Author(s):  
Yo Otsu ◽  
Eiichi Maru ◽  
Hisayuki Ohata ◽  
Ichiro Takashima ◽  
Riichi Kajiwara ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Molecular Layer ◽  
Mossy Fibers ◽  
Optical Recording ◽  
Granule Cell Layer ◽  
Gabaergic Inhibition ◽  
Mossy Fiber Sprouting

In the epileptic hippocampus, newly sprouted mossy fibers are considered to form recurrent excitatory connections to granule cells in the dentate gyrus and thereby increase seizure susceptibility. To study the effects of mossy fiber sprouting on neural activity in individual lamellae of the dentate gyrus, we used high-speed optical recording to record signals from voltage-sensitive dye in hippocampal slices prepared from kainate-treated epileptic rats (KA rats). In 14 of 24 slices from KA rats, hilar stimulation evoked a large depolarization in almost the entire molecular layer in which granule cell apical dendrites are located. The signals were identified as postsynaptic responses because of their dependence on extracellular Ca2+. The depolarization amplitude was largest in the inner molecular layer (the target area of sprouted mossy fibers) and declined with increasing distance from the granule cell layer. In the inner molecular layer, a good correlation was obtained between depolarization size and the density of mossy fiber terminals detected by Timm staining methods. Blockade of GABAergic inhibition by bicuculline enlarged the depolarization in granule cell dendrites. Our data indicate that mossy fiber sprouting results in a large and prolonged synaptic depolarization in an extensive dendritic area and that the enhanced GABAergic inhibition partly masks the synaptic depolarization. However, despite the large dendritic excitation induced by the sprouted mossy fibers, seizurelike activity of granule cells was never observed, even when GABAergic inhibition was blocked. Therefore, mossy fiber sprouting may not play a critical role in epileptogenesis.

scholarly journals Morphological constraints on cerebellar granule cell combinatorial diversity

2017 ◽  
Author(s):  
Jesse I. Gilmer ◽  
Abigail L. Person
Keyword(s):  
Granule Cell ◽  
Granule Cells ◽  
Cell Layer ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Cerebellar Granule Cell ◽  
Granule Cell Layer ◽  
Information Encoding ◽  
Cerebellar Granule ◽  
Local Sampling

AbstractCombinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar granule cell layer and examined how GCL architecture contributes to granule cell (GrC) combinatorial diversity. We found that GrC combinatorial diversity saturates quickly as mossy fiber input diversity increases, and that this saturation is in part a consequence of short dendrites, which limit access to diverse inputs and favor dense sampling of local inputs. This local sampling also produced GrCs that were combinatorially redundant, even when input diversity was extremely high. In addition, we found that mossy fibers clustering, which is a common anatomical pattern, also led to increased redundancy of GrC input combinations. We related this redundancy to hypothesized roles of temporal expansion of GrC information encoding in service of learned timing, and show that GCL architecture produces GrC populations that support both temporal and combinatorial expansion. Finally, we used novel anatomical measurements from mice of either sex to inform modeling of sparse and filopodia-bearing mossy fibers, finding that these circuit features uniquely contribute to enhancing GrC diversification and redundancy. Our results complement information theoretic studies of granule layer structure and provide insight into the contributions of granule layer anatomical features to afferent mixing.Significance StatementCerebellar granule cells are among the simplest neurons, with tiny somata and on average just four dendrites. These characteristics, along with their dense organization, inspired influential theoretical work on the granule cell layer (GCL) as a combinatorial expander, where each granule cell represents a unique combination of inputs. Despite the centrality of these theories to cerebellar physiology, the degree of expansion supported by anatomically realistic patterns of inputs is unknown. Using modeling and anatomy, we show that realistic input patterns constrain combinatorial diversity by producing redundant combinations, which nevertheless could support temporal diversification of like-combinations, suitable for learned timing. Our study suggests a neural substrate for producing high levels of both combinatorial and temporal diversity in the GCL.

scholarly journals Efficient generation of reciprocal signals by inhibition

2012 ◽  
Vol 107 (9) ◽  
pp. 2453-2462 ◽  
Author(s):  
Sung-min Park ◽  
Esra Tara ◽  
Kamran Khodakhah
Keyword(s):  
Purkinje Cells ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Cell Activity ◽  
Common Mechanism ◽  
Input Output ◽  
Firing Rates ◽  
Neuronal Computation ◽  
The Brain

Reciprocal activity between populations of neurons has been widely observed in the brain and is essential for neuronal computation. The different mechanisms by which reciprocal neuronal activity is generated remain to be established. A common motif in neuronal circuits is the presence of afferents that provide excitation to one set of principal neurons and, via interneurons, inhibition to a second set of principal neurons. This circuitry can be the substrate for generation of reciprocal signals. Here we demonstrate that this equivalent circuit in the cerebellar cortex enables the reciprocal firing rates of Purkinje cells to be efficiently generated from a common set of mossy fiber inputs. The activity of a mossy fiber is relayed to Purkinje cells positioned immediately above it by excitatory granule cells. The firing rates of these Purkinje cells increase as a linear function of mossy fiber, and thus granule cell, activity. In addition to exciting Purkinje cells positioned immediately above it, the activity of a mossy fiber is relayed to laterally positioned Purkinje cells by a disynaptic granule cell → molecular layer interneuron pathway. Here we show in acutely prepared cerebellar slices that the input-output relationship of these laterally positioned Purkinje cells is linear and reciprocal to the first set. A similar linear input-output relationship between decreases in Purkinje cell firing and strength of stimulation of laterally positioned granule cells was also observed in vivo. Use of interneurons to generate reciprocal firing rates may be a common mechanism by which the brain generates reciprocal signals.

scholarly journals Stereotyped spatial patterns of functional synaptic connectivity in the cerebellar cortex

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Antoine M Valera ◽  
Francesca Binda ◽  
Sophie A Pawlowski ◽  
Jean-Luc Dupont ◽  
Jean-François Casella ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Cerebellar Cortex ◽  
Granule Cell ◽  
Motor Coordination ◽  
Molecular Layer ◽  
Granule Cell Layer ◽  
Synaptic Organization ◽  
Cerebellar Modules ◽  
Activity Dependent

Motor coordination is supported by an array of highly organized heterogeneous modules in the cerebellum. How incoming sensorimotor information is channeled and communicated between these anatomical modules is still poorly understood. In this study, we used transgenic mice expressing GFP in specific subsets of Purkinje cells that allowed us to target a given set of cerebellar modules. Combining in vitro recordings and photostimulation, we identified stereotyped patterns of functional synaptic organization between the granule cell layer and its main targets, the Purkinje cells, Golgi cells and molecular layer interneurons. Each type of connection displayed position-specific patterns of granule cell synaptic inputs that do not strictly match with anatomical boundaries but connect distant cortical modules. Although these patterns can be adjusted by activity-dependent processes, they were found to be consistent and predictable between animals. Our results highlight the operational rules underlying communication between modules in the cerebellar cortex.

scholarly journals Recruitment of an inhibitory hippocampal network after bursting in a single granule cell

2007 ◽  
Vol 104 (18) ◽  
pp. 7640-7645 ◽  
Author(s):  
Masahiro Mori ◽  
Beat H. Gähwiler ◽  
Urs Gerber
Keyword(s):  
Pyramidal Cell ◽  
Granule Cell ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Pyramidal Cells ◽  
Network Activity ◽  
Inhibitory Input ◽  
Inhibitory Interneurons ◽  
Failure Rates ◽  
Ca3 Pyramidal Cells

The hippocampal CA3 area, an associational network implicated in memory function, receives monosynaptic excitatory as well as disynaptic inhibitory input through the mossy-fiber axons of the dentate granule cells. Synapses made by mossy fibers exhibit low release probability, resulting in high failure rates at resting discharge frequencies of 0.1 Hz. In recordings from functionally connected pairs of neurons, burst firing of a granule cell increased the probability of glutamate release onto both CA3 pyramidal cells and inhibitory interneurons, such that subsequent low-frequency stimulation evoked biphasic excitatory/inhibitory responses in a CA3 pyramidal cell, an effect lasting for minutes. Analysis of the unitary connections in the circuit revealed that granule cell bursting caused powerful activation of an inhibitory network, thereby transiently suppressing excitatory input to CA3 pyramidal cells. This phenomenon reflects the high incidence of spike-to-spike transmission at granule cell to interneuron synapses, the numerically much greater targeting by mossy fibers of inhibitory interneurons versus principal cells, and the extensively divergent output of interneurons targeting CA3 pyramidal cells. Thus, mossy-fiber input to CA3 pyramidal cells appears to function in three distinct modes: a resting mode, in which synaptic transmission is ineffectual because of high failure rates; a bursting mode, in which excitation predominates; and a postbursting mode, in which inhibitory input to the CA3 pyramidal cells is greatly enhanced. A mechanism allowing the transient recruitment of inhibitory input may be important for controlling network activity in the highly interconnected CA3 pyramidal cell region.

Trigeminocerebellar mossy fiber branching to granule cell layer patches in the rat cerebellum

1981 ◽  
Vol 209 (2) ◽  
pp. 255-269 ◽  
Author(s):  
Donald C. Woolston ◽  
Jeffrey Kassel ◽  
John M. Gibson
Keyword(s):  
Granule Cell ◽  
Cell Layer ◽  
Mossy Fiber ◽  
Granule Cell Layer ◽  
Rat Cerebellum

scholarly journals Dynamics and function of CXCR4 in formation of the granule cell layer during hippocampal development

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuka Mimura-Yamamoto ◽  
Hiroshi Shinohara ◽  
Taichi Kashiwagi ◽  
Toru Sato ◽  
Seiji Shioda ◽  
...  
Keyword(s):  
Granule Cell ◽  
Cell Layer ◽  
Granule Cell Layer ◽  
Hippocampal Development ◽  
Dynamics And Function ◽  
And Function

Effect of Conditioned Stimulus Parameters on Timing of Conditioned Purkinje Cell Responses

2010 ◽  
Vol 103 (3) ◽  
pp. 1329-1336 ◽  
Author(s):  
Pär Svensson ◽  
Dan-Anders Jirenhed ◽  
Fredrik Bengtsson ◽  
Germund Hesslow
Keyword(s):  
Conditioned Stimulus ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Mossy Fiber ◽  
Eyeblink Conditioning ◽  
Mossy Fibers ◽  
Inhibitory Response ◽  
Cell Responses ◽  
Cerebellar Purkinje Cells ◽  
Adaptive Timing

Pavlovian eyeblink conditioning is a useful experimental model for studying adaptive timing, an important aspect of skilled movements. The conditioned response (CR) is precisely timed to occur just before the onset of the expected unconditioned stimulus (US). The timing can be changed immediately, however, by varying parameters of the conditioned stimulus (CS). It has previously been shown that increasing the intensity of a peripheral CS or the frequency of a CS consisting of a train of stimuli to the mossy fibers shortens the latency of the CR. The adaptive timing of behavioral CRs probably reflects the timing of an underlying learned inhibitory response in cerebellar Purkinje cells. It is not known how the latency of this Purkinje cell CR is controlled. We have recorded form Purkinje cells in conditioned decerebrate ferrets while increasing the intensity of a peripheral CS or the frequency of a mossy fiber CS. We observe changes in the timing of the Purkinje cell CR that match the behavioral effects. The results are consistent with the effect of CS parameters on behavioral CR latency being caused by corresponding changes in Purkinje cell CRs. They suggest that synaptic temporal summation may be one of several mechanisms underlying adaptive timing of movements.

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