scholarly journals Impact of parallel fiber to Purkinje cell long-term depression is unmasked in absence of inhibitory input

2018 ◽  
Vol 4 (10) ◽  
pp. eaas9426 ◽  
Author(s):  
Henk-Jan Boele ◽  
Saša Peter ◽  
Michiel M. Ten Brinke ◽  
Lucas Verdonschot ◽  
Anna C. H. IJpelaar ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Eyeblink Conditioning ◽  
Molecular Layer ◽  
Learning Task ◽  
Parallel Fiber ◽  
Neural Mechanisms ◽  
Inhibitory Input ◽  
Long Term Depression ◽  
Feed Forward Inhibition

Pavlovian eyeblink conditioning has been used extensively to study the neural mechanisms underlying associative and motor learning. During this simple learning task, memory formation takes place at Purkinje cells in defined areas of the cerebellar cortex, which acquire a strong temporary suppression of their activity during conditioning. Yet, it is unknown which neuronal plasticity mechanisms mediate this suppression. Two potential mechanisms include long-term depression of parallel fiber to Purkinje cell synapses and feed-forward inhibition by molecular layer interneurons. We show, using a triple transgenic approach, that only concurrent disruption of both these suppression mechanisms can severely impair conditioning, highlighting that both processes can compensate for each other’s deficits.

scholarly journals Purkinje cell intrinsic excitability increases after synaptic long term depression

2016 ◽  
Vol 116 (3) ◽  
pp. 1208-1217 ◽  
Author(s):  
Zhen Yang ◽  
Fidel Santamaria
Keyword(s):  
Purkinje Cell ◽  
Purkinje Cells ◽  
Input Resistance ◽  
Parallel Fiber ◽  
Intrinsic Excitability ◽  
Hcn Channel ◽  
Membrane Excitability ◽  
Fiber System ◽  
Long Term Depression

Coding in cerebellar Purkinje cells not only depends on synaptic plasticity but also on their intrinsic membrane excitability. We performed whole cell patch-clamp recordings of Purkinje cells in sagittal cerebellar slices in mice. We found that inducing long-term depression (LTD) in the parallel fiber to Purkinje cell synapses results in an increase in the gain of the firing rate response. This increase in excitability is accompanied by an increase in the input resistance and a decrease in the amplitude of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated voltage sag. Application of a HCN channel blocker prevents the increase in input resistance and excitability without blocking the expression of synaptic LTD. We conclude that the induction of parallel fiber-Purkinje cell LTD is accompanied by an increase in excitability of Purkinje cells through downregulation of the HCN-mediated h current. We suggest that HCN downregulation is linked to the biochemical pathway that sustains synaptic LTD. Given the diversity of information carried by the parallel fiber system, we suggest that changes in intrinsic excitability enhance the coding capacity of the Purkinje cell to specific input sources.

scholarly journals Alcohol Impairs Long-Term Depression at the Cerebellar Parallel Fiber–Purkinje Cell Synapse

2008 ◽  
Vol 100 (6) ◽  
pp. 3167-3174 ◽  
Author(s):  
Amor Belmeguenai ◽  
Paolo Botta ◽  
John T. Weber ◽  
Mario Carta ◽  
Martijn De Ruiter ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Motor Learning ◽  
Synaptic Transmission ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Motor Coordination ◽  
Parallel Fiber ◽  
Calcium Currents ◽  
Long Term Depression

Acute alcohol consumption causes deficits in motor coordination and gait, suggesting an involvement of cerebellar circuits, which play a role in the fine adjustment of movements and in motor learning. It has previously been shown that ethanol modulates inhibitory transmission in the cerebellum and affects synaptic transmission and plasticity at excitatory climbing fiber (CF) to Purkinje cell synapses. However, it has not been examined thus far how acute ethanol application affects long-term depression (LTD) and long-term potentiation (LTP) at excitatory parallel fiber (PF) to Purkinje cell synapses, which are assumed to mediate forms of cerebellar motor learning. To examine ethanol effects on PF synaptic transmission and plasticity, we performed whole cell patch-clamp recordings from Purkinje cells in rat cerebellar slices. We found that ethanol (50 mM) selectively blocked PF–LTD induction, whereas it did not change the amplitude of excitatory postsynaptic currents at PF synapses. In contrast, ethanol application reduced voltage-gated calcium currents and type 1 metabotropic glutamate receptor (mGluR1)–dependent responses in Purkinje cells, both of which are involved in PF–LTD induction. The selectivity of these effects is emphasized by the observation that ethanol did not impair PF–LTP and that PF–LTP could readily be induced in the presence of the group I mGluR antagonist AIDA or the mGluR1a antagonist LY367385. Taken together, these findings identify calcium currents and mGluR1-dependent signaling pathways as potential ethanol targets and suggest that an ethanol-induced blockade of PF–LTD could contribute to the motor coordination deficits resulting from alcohol consumption.

scholarly journals Lgr4 Protein Deficiency Induces Ataxia-like Phenotype in Mice and Impairs Long Term Depression at Cerebellar Parallel Fiber-Purkinje Cell Synapses

2014 ◽  
Vol 289 (38) ◽  
pp. 26492-26504 ◽  
Author(s):  
Xin Guan ◽  
Yanhong Duan ◽  
Qingwen Zeng ◽  
Hongjie Pan ◽  
Yu Qian ◽  
...  
Keyword(s):  
Purkinje Cell ◽  
Parallel Fiber ◽  
Protein Deficiency ◽  
Long Term Depression

scholarly journals Dendritic Excitability Microzones and Occluded Long-Term Depression After Classical Conditioning of the Rabbit's Nictitating Membrane Response

1997 ◽  
Vol 77 (1) ◽  
pp. 86-92 ◽  
Author(s):  
Bernard G. Schreurs ◽  
Daniel Tomsic ◽  
Pavel A. Gusev ◽  
Daniel L. Alkon
Keyword(s):  
Classical Conditioning ◽  
Purkinje Cell ◽  
Purkinje Cells ◽  
Parallel Fiber ◽  
Long Term Depression ◽  
Nictitating Membrane Response ◽  
Fiber Stimulation ◽  
In Cells

Schreurs, Bernard G., Daniel Tomsic, Pavel A. Gusev, and Daniel L. Alkon. Dendritic excitability microzones and occluded long-term depression after classical conditioning of the rabbit's nictitating membrane response. J. Neurophysiol. 77: 86–92, 1997. We made intradendritic recordings in Purkinje cells ( n = 164) from parasaggital slices of cerebellar lobule HVI obtained from rabbits given paired presentations of tone and periorbital electrical stimulation (classical conditioning, n = 27) or explicitly unpaired presentations of tone and periorbital stimulation (control, n = 16). Purkinje cell dendritic membrane excitability, assessed by the current required to elicit local dendritic calcium spikes, increased significantly in slices from animals that received classical conditioning. In contrast, membrane potential, input resistance, and amplitude of somatic and dendritic spikes were not different in slices from animals given paired or explicitly unpaired stimulus presentations. The location of cells with low thresholds for local dendritic calcium spikes suggested that there are specific sites for learning-related changes within lobule HVI. These areas may correspond to learning “microzones” and are consistent with locations of learning-related in vivo changes in Purkinje cell activity. Application of 4-aminopyridine, an antagonist of the rapidly inactivating potassium current I A, reduced the threshold for dendritic spikes in slices from naive animals to levels found in slices from trained animals. In cells where thresholds for eliciting parallel fiber–stimulated Purkinje cell excitatory postsynaptic potentials (EPSPs) were measured, levels of parallel fiber stimulation required to elicit a 6-mV EPSP as well as a 4-mV EPSP ( n = 30) and a Purkinje cell spike ( n = 56) were found to be significantly lower in slices from paired animals than unpaired controls. A classical conditioning procedure was simulated in slices of lobule HVI by pairing a brief, high-frequency train of parallel fiber stimulation (8 pulses, 100 Hz) with a brief, lower frequency train of climbing fiber stimulation (3 pulses, 20 Hz) to the same Purkinje cell. Following paired stimulation of the parallel and climbing fibers, Purkinje cell EPSPs underwent a long-term (>20 min) reduction in peak amplitude (−24%) in cells ( n = 12) from animals given unpaired stimulus presentations but to a far less extent (−9%) in cells ( n = 20) from animals given in vivo paired training. Whereas 92% of cells from unpaired animals showed pairing-specific depression, 50% of cells from paired animals showed no depression and in several cases showed potentiation. Our data establish that there are localized learning-specific changes in membrane and synaptic excitability of Purkinje cells in rabbit lobule HVI that can be detected in slices 24 h after classical conditioning. Long-term changes within Purkinje cells that effect this enhanced excitability may occlude pairing-specific long-term depression.

Pairing-specific long-term depression of Purkinje cell excitatory postsynaptic potentials results from a classical conditioning procedure in the rabbit cerebellar slice

1996 ◽  
Vol 75 (3) ◽  
pp. 1051-1060 ◽  
Author(s):  
B. G. Schreurs ◽  
M. M. Oh ◽  
D. L. Alkon
Keyword(s):  
Classical Conditioning ◽  
Purkinje Cell ◽  
Climbing Fiber ◽  
Parallel Fiber ◽  
Peak Amplitude ◽  
Constant Current ◽  
Long Term Depression ◽  
Paired Stimulation

1. Using a rabbit cerebellar slice preparation, we stimulated a classical conditioning procedure by stimulating parallel fiber inputs to Purkinje cells with the use of a brief, high-frequency train of eight constant-current pulses 80 ms before climbing fiber inputs to the same Purkinje cell were stimulated with the use of a brief, lower frequency train of three constant-current pulses. In all experiments, we assessed the effects of stimulation by measuring the peak amplitude of Purkinje cell excitatory postsynaptic potentials (EPSPs) to single parallel fiber test pulses. 2. Intradendritically recorded Purkinje cell EPSPs underwent a long-term (> 20 min) reduction in peak amplitude (30%) after paired stimulation of the parallel and climbing fibers but not after unpaired or parallel fiber alone stimulation. We call this phenomenon pairing-specific long-term depression (PSD). 3. Facilitation of the peak amplitude of a second EPSP elicited by a parallel fiber train occurred both before and after paired stimulation suggesting that the locus of depression was not presynaptic. Depression of the peak amplitude of a depolarizing response to focal application of glutamate following pairings of parallel and climbing fiber stimulation added support to a suggested postsynaptic locus of the PSD effect. 4. The application of aniracetam potentiated EPSP peak amplitude by 40%, but these values returned to baseline as a result of pairings. With the removal of aniracetam from the bath 20 min after pairings, normal levels of pairing-specific EPSP depression were observed, indicating that the effect did not result from direct desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptors. 5. Incubation of slices in the protein kinase inhibitor H-7 potentiated EPSP peak amplitudes slightly (9%), but peak amplitudes returned to baseline levels after pairings. The net reduction in EPSP peak amplitude of < 10% after pairings suggested that H-7 partially blocked PSD and that, in turn, PSD involved protein kinases. 6. The means of induction and the specificity of those means suggest that the phenomenology of PSD is fundamentally different from that of long-term depression. PSD only occurs with pairings of trains of parallel fiber and climbing fiber stimulation; it occurs without the need for bicuculline; and it can overcome the blocking effects of aniracetam. 7. Nevertheless, the involvement of protein kinases and the potential role of calcium suggest that the mechanisms involved in the induction of PSD and long-term depression have a number of features in common. 8. Because of the pairing-specific nature of the long-term synaptic depression observed in these experiments, PSD provides a mechanism that may contribute to the role of the cerebellar cortex in classical conditioning.

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