scholarly journals GluA4 facilitates cerebellar expansion coding and enables associative memory formation

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Katarzyna Kita ◽  
Catarina Albergaria ◽  
Ana S Machado ◽  
Megan R Carey ◽  
Martin Mueller ◽  
...  
Keyword(s):  
Associative Learning ◽  
Associative Memory ◽  
Granule Cell ◽  
Ampa Receptors ◽  
Knockout Mice ◽  
Mossy Fiber ◽  
Eyeblink Conditioning ◽  
Memory Formation ◽  
Synaptic Excitation ◽  
Excitatory Neurotransmission

AMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ~80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational network modeling incorporating these changes revealed that deletion of GluA4 impairs granule cell expansion coding, which is important for pattern separation and associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

scholarly journals GluA4 enables associative memory formation by facilitating cerebellar expansion coding

2020 ◽  
Author(s):  
Katarzyna Kita ◽  
Catarina Albergaria ◽  
Ana S. Machado ◽  
Megan R. Carey ◽  
Martin Müller ◽  
...  
Keyword(s):  
Associative Learning ◽  
Associative Memory ◽  
Granule Cell ◽  
Ampa Receptors ◽  
Knockout Mice ◽  
Mossy Fiber ◽  
Eyeblink Conditioning ◽  
Memory Formation ◽  
Synaptic Excitation ◽  
Excitatory Neurotransmission

AbstractAMPA receptors (AMPARs) mediate excitatory neurotransmission in the CNS and their subunit composition determines synaptic efficacy. Whereas AMPAR subunits GluA1–GluA3 have been linked to particular forms of synaptic plasticity and learning, the functional role of GluA4 remains elusive. Here we used electrophysiological, computational and behavioral approaches to demonstrate a crucial function of GluA4 for synaptic excitation and associative memory formation in the cerebellum. Notably, GluA4-knockout mice had ∼80% reduced mossy fiber to granule cell synaptic transmission. The fidelity of granule cell spike output was markedly decreased despite attenuated tonic inhibition and increased NMDA receptor-mediated transmission. Computational modeling revealed that GluA4 facilitates pattern separation that is important for associative learning. On a behavioral level, while locomotor coordination was generally spared, GluA4-knockout mice failed to form associative memories during delay eyeblink conditioning. These results demonstrate an essential role for GluA4-containing AMPARs in cerebellar information processing and associative learning.

scholarly journals High Ratio of Synaptic Excitation to Synaptic Inhibition in Hilar Ectopic Granule Cells of Pilocarpine-Treated Rats

2010 ◽  
Vol 104 (6) ◽  
pp. 3293-3304 ◽  
Author(s):  
Ren-Zhi Zhan ◽  
Olga Timofeeva ◽  
J. Victor Nadler
Keyword(s):  
Status Epilepticus ◽  
Granule Cell ◽  
Granule Cells ◽  
Mossy Fiber ◽  
High Ratio ◽  
Synaptic Function ◽  
Excitatory Postsynaptic Currents ◽  
Inhibitory Postsynaptic Currents ◽  
Synaptic Excitation ◽  
Postsynaptic Currents

After experimental status epilepticus, many dentate granule cells born into the postseizure environment migrate aberrantly into the dentate hilus. Hilar ectopic granule cells (HEGCs) have also been found in persons with epilepsy. These cells exhibit a high rate of spontaneous activity, which may enhance seizure propagation. Electron microscopic studies indicated that HEGCs receive more recurrent mossy fiber innervation than normotopic granule cells in the same animals but receive much less inhibitory innervation. This study used hippocampal slices prepared from rats that had experienced pilocarpine-induced status epilepticus to test the hypothesis that an imbalance of synaptic excitation and inhibition contributes to the hyperexcitability of HEGCs. Mossy fiber stimulation evoked a much smaller GABAA receptor–mediated inhibitory postsynaptic currents (IPSC) in HEGCs than in normotopic granule cells from either control rats or rats that had experienced status epilepticus. However, recurrent mossy fiber-evoked excitatory postsynaptic currents (EPSCs) of similar size were recorded from HEGCs and normotopic granule cells in status epilepticus–experienced rats. HEGCs exhibited the highest frequency of miniature excitatory postsynaptic currents (mEPSCs) and the lowest frequency of miniature inhibitory postsynaptic currents (mIPSCs) of any granule cell group. On average, both mEPSCs and mIPSCs were of higher amplitude, transferred more charge per event, and exhibited slower kinetics in HEGCs than in granule cells from control rats. Charge transfer per unit time in HEGCs was greater for mEPSCs and much less for mIPSCs than in the normotopic granule cell groups. A high ratio of excitatory to inhibitory synaptic function probably accounts, in part, for the hyperexcitability of HEGCs.

scholarly journals Desensitization Properties of AMPA Receptors at the Cerebellar Mossy Fiber Granule Cell Synapse

2007 ◽  
Vol 27 (31) ◽  
pp. 8344-8357 ◽  
Author(s):  
D. A. DiGregorio ◽  
J. S. Rothman ◽  
T. A. Nielsen ◽  
R. A. Silver
Keyword(s):  
Granule Cell ◽  
Ampa Receptors ◽  
Mossy Fiber ◽  
Cell Synapse

scholarly journals Associative memory cells: Formation, function and perspective

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 283 ◽  
Author(s):  
Jin-Hui Wang ◽  
Shan Cui
Keyword(s):  
Associative Learning ◽  
Learning And Memory ◽  
Associative Memory ◽  
Cognitive Processes ◽  
Neuronal Plasticity ◽  
Memory Formation ◽  
Memory Cells ◽  
Storage And Retrieval ◽  
Formation Function ◽  
Sensory Cortices

Associative learning and memory are common activities in life, and their cellular infrastructures constitute the basis of cognitive processes. Although neuronal plasticity emerges after memory formation, basic units and their working principles for the storage and retrieval of associated signals remain to be revealed. Current reports indicate that associative memory cells, through their mutual synapse innervations among the co-activated sensory cortices, are recruited to fulfill the integration, storage and retrieval of multiple associated signals, and serve associative thinking and logical reasoning. In this review, we aim to summarize associative memory cells in their formation, features and functional impacts.

scholarly journals Associative memory cells: Formation, function and perspective

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 283 ◽  
Author(s):  
Jin-Hui Wang ◽  
Shan Cui
Keyword(s):  
Associative Learning ◽  
Learning And Memory ◽  
Associative Memory ◽  
Cognitive Processes ◽  
Neuronal Plasticity ◽  
Memory Formation ◽  
Memory Cells ◽  
Storage And Retrieval ◽  
Formation Function ◽  
Sensory Cortices

Associative learning and memory are common activities in life, and their cellular infrastructures constitute the basis of cognitive processes. Although neuronal plasticity emerges after memory formation, basic units and their working principles for the storage and retrieval of associated signals remain to be revealed. Current reports indicate that associative memory cells, through their mutual synapse innervations among the co-activated sensory cortices, are recruited to fulfill the integration, storage and retrieval of multiple associated signals, and serve associative thinking and logical reasoning. In this review, we aim to summarize associative memory cells in their formation, features and functional impacts.

scholarly journals Locomotor activity modulates associative learning in mouse cerebellum

2017 ◽  
Author(s):  
Catarina Albergaria ◽  
N. Tatiana Silva ◽  
Dominique Pritchett ◽  
Megan R. Carey
Keyword(s):  
Locomotor Activity ◽  
Associative Learning ◽  
Cerebellar Cortex ◽  
Mossy Fiber ◽  
Eyeblink Conditioning ◽  
Sensory Modality ◽  
Behavioral State ◽  
Dependent Form ◽  
Conditioned Responses ◽  
Sensory Responses

AbstractChanges in behavioral state are associated with modulation of sensory responses across visual, auditory and somatosensory cortices. Here we show that locomotor activity independently modulates performance in delay eyeblink conditioning, a cerebellum-dependent form of associative learning. Increased locomotor speed in head-fixed mice was associated with earlier onset of learning and trial-by-trial enhancement of learned responses. The influence of locomotion on conditioned responses was dissociable from changes in arousal and was independent of the sensory modality of the conditioned stimulus. Eyelid responses evoked by optogenetic stimulation of mossy fiber terminals within the cerebellar cortex, but not at sites downstream, were also positively modulated by ongoing locomotion. We conclude that locomotor activity modulates delay eyeblink conditioning through mechanisms acting on the mossy fiber pathway within the cerebellar cortex. Taken together, these results suggest a novel role for behavioral state modulation in associative learning and provide a potential mechanism through which engaging in movement can improve an individual’s ability to learn.

scholarly journals Synaptic abnormalities and cytoplasmic glutamate receptor aggregates in contactin associated protein-like 2/Caspr2 knockout neurons

2015 ◽  
Vol 112 (19) ◽  
pp. 6176-6181 ◽  
Author(s):  
Olga Varea ◽  
Maria Dolores Martin-de-Saavedra ◽  
Katherine J. Kopeikina ◽  
Britta Schürmann ◽  
Hunter J. Fleming ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Knockout Mice ◽  
Copy Number Variations ◽  
Spine Density ◽  
Structured Illumination ◽  
Single Nucleotide Variants ◽  
Glutamatergic Synapses ◽  
Superresolution Microscopy ◽  
Synaptic Markers ◽  
Cellular Phenotypes

Central glutamatergic synapses and the molecular pathways that control them are emerging as common substrates in the pathogenesis of mental disorders. Genetic variation in the contactin associated protein-like 2 (CNTNAP2) gene, including copy number variations, exon deletions, truncations, single nucleotide variants, and polymorphisms have been associated with intellectual disability, epilepsy, schizophrenia, language disorders, and autism. CNTNAP2, encoded by Cntnap2, is required for dendritic spine development and its absence causes disease-related phenotypes in mice. However, the mechanisms whereby CNTNAP2 regulates glutamatergic synapses are not known, and cellular phenotypes have not been investigated in Cntnap2 knockout neurons. Here we show that CNTNAP2 is present in dendritic spines, as well as axons and soma. Structured illumination superresolution microscopy reveals closer proximity to excitatory, rather than inhibitory synaptic markers. CNTNAP2 does not promote the formation of synapses and cultured neurons from Cntnap2 knockout mice do not show early defects in axon and dendrite outgrowth, suggesting that CNTNAP2 is not required at this stage. However, mature neurons from knockout mice show reduced spine density and levels of GluA1 subunits of AMPA receptors in spines. Unexpectedly, knockout neurons show large cytoplasmic aggregates of GluA1. Here we characterize, for the first time to our knowledge, synaptic phenotypes in Cntnap2 knockout neurons and reveal a novel role for CNTNAP2 in GluA1 trafficking. Taken together, our findings provide insight into the biological roles of CNTNAP2 and into the pathogenesis of CNTNAP2-associated neuropsychiatric disorders.

How Synaptic Release Probability Shapes Neuronal Transmission: Information-Theoretic Analysis in a Cerebellar Granule Cell

2010 ◽  
Vol 22 (8) ◽  
pp. 2031-2058 ◽  
Author(s):  
Angelo Arleo ◽  
Thierry Nieus ◽  
Michele Bezzi ◽  
Anna D'Errico ◽  
Egidio D'Angelo ◽  
...  
Keyword(s):  
Information Transmission ◽  
Numerical Simulations ◽  
Granule Cell ◽  
Mossy Fiber ◽  
Dendritic Tree ◽  
Long Term Potentiation ◽  
Cerebellar Granule Cell ◽  
Information Theoretic ◽  
Cerebellar Granule ◽  
Release Probability

A nerve cell receives multiple inputs from upstream neurons by way of its synapses. Neuron processing functions are thus influenced by changes in the biophysical properties of the synapse, such as long-term potentiation (LTP) or depression (LTD). This observation has opened new perspectives on the biophysical basis of learning and memory, but its quantitative impact on the information transmission of a neuron remains partially elucidated. One major obstacle is the high dimensionality of the neuronal input-output space, which makes it unfeasible to perform a thorough computational analysis of a neuron with multiple synaptic inputs. In this work, information theory was employed to characterize the information transmission of a cerebellar granule cell over a region of its excitatory input space following synaptic changes. Granule cells have a small dendritic tree (on average, they receive only four mossy fiber afferents), which greatly bounds the input combinatorial space, reducing the complexity of information-theoretic calculations. Numerical simulations and LTP experiments quantified how changes in neurotransmitter release probability (p) modulated information transmission of a cerebellar granule cell. Numerical simulations showed that p shaped the neurotransmission landscape in unexpected ways. As p increased, the optimality of the information transmission of most stimuli did not increase strictly monotonically; instead it reached a plateau at intermediate p levels. Furthermore, our results showed that the spatiotemporal characteristics of the inputs determine the effect of p on neurotransmission, thus permitting the selection of distinctive preferred stimuli for different p values. These selective mechanisms may have important consequences on the encoding of cerebellar mossy fiber inputs and the plasticity and computation at the next circuit stage, including the parallel fiber–Purkinje cell synapses.

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.

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