Feed‐forward inhibition shapes the spike output of cerebellar Purkinje cells

Mittmann, Wolfgang; Koch, Ursula; Häusser, Michael

doi:10.1113/jphysiol.2004.075028

Cited by 288 publications

(332 citation statements)

References 45 publications

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“…In a possible scenario repetitive action potentials from the parallel fibers, like those that occur in vivo (18), could activate glutamatergic synapses onto Purkinje cells to produce a short excitation that would put the on-beam Purkinje cells in an up state regardless of their previous state. The feed-forward inhibition that would then follow (31,32) would switch these on-beam Purkinje cells into a down state, whereas off-beam Purkinje cells, that do not receive the short excitation provided by parallel fibers, would switch states. Our experiments using cell-attached recording techniques suggest that although the switch from up to down states would occur in nearly every cell, approximately a third of the off-beam Purkinje cells would switch to an up state.…”

Section: Discussionmentioning

confidence: 99%

Interneurons of the cerebellar cortex toggle Purkinje cells between up and down states

Oldfield

Marty

Stell

2010

Proc. Natl. Acad. Sci. U.S.A.

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We demonstrate that single interneurons can toggle the output neurons of the cerebellar cortex (the Purkinje cells) between their two states. The firing of Purkinje cells has previously been shown to alternate between an "up" state in which the cell fires spontaneous action potentials and a silent "down" state. We show here that small hyperpolarizing currents in Purkinje cells can bidirectionally toggle Purkinje cells between down and up states and that blockade of the hyperpolarization-activated cation channels (H channels) with the specific antagonist ZD7288 (10 μM) blocks the transitions from down to up states. Likewise, hyperpolarizing inhibitory postsnyaptic potentials (IPSPs) produced by small bursts of action potentials (10 action potentials at 50 Hz) in molecularlayer interneurons induce these bidirectional transitions in Purkinje cells. Furthermore, single interneurons in paired interneuron → Purkinje cell recordings, produce bidirectional switches between the two states of Purkinje cells. The ability of molecular-layer interneurons to toggle Purkinje cells occurs when Purkinje cells are recorded under whole-cell patch-clamp conditions as well as when action potentials are recorded in an extracellular loose cell-attached configuration. The mode switch demonstrated here indicates that a single presynaptic interneuron can have opposite effects on the output of a given Purkinje cell, which introduces a unique type of synaptic interaction that may play an important role in cerebellar signaling.A s the sole output of the cerebellar cortex, Purkinje cells are ultimately responsible for relaying the computation performed by the entire network. Even though membrane properties and synaptic currents have been extensively studied in the cerebellar circuit, it still remains unclear how Purkinje cells process information coming from the rest of the cerebellar cortex before passing it on to the deep cerebellar nuclei. Purkinje cells are known to intrinsically generate action potentials at high rates and also to have an intrinsic membrane bistability (1-4). The cell switches between hyperpolarized potentials during which it is silent and depolarized potentials during which it fires action potentials (1, 2, 5-11). The frequency of changes between the two states in awake versus anesthetized animals in vivo has been disputed, but it is agreed that the bistability exists in a fraction of Purkinje cells in both anesthetized and unanesthetized animals (5, 6). This unique characteristic of the output of Purkinje cells potentially plays a significant role in passing the computation of the cerebellar cortex onto the cerebellar nuclei. Therefore to understand how Purkinje cells process this information it is essential to understand how the cells within the cerebellar cortex influence this bistable output of Purkinje cells.The climbing fibers, which provide glutamatergic inputs to Purkinje cells from outside the cerebellar cortex, have been shown to produce complex spikes in Purkinje cells (1). In experiments performed in vivo a...

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Section: Discussionmentioning

confidence: 99%

Interneurons of the cerebellar cortex toggle Purkinje cells between up and down states

Oldfield

Marty

Stell

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Temporal summation of parallel fiber EPSPs has also been shown to be controlled through feed-forward inhibition (33). However, when we repeated these tests in coronal slices in the absence of picrotoxin to preserve feed-forward inhibition, TRAM-34 rapidly increased temporal summation of parallel fiber-evoked EPSPs (Fig.…”

Section: Cav3-kca31 Interaction Controls Temporal Summation Of Parallelmentioning

confidence: 99%

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

Engbers

Anderson²,

Asmara³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

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Encoding sensory input requires the expression of postsynaptic ion channels to transform key features of afferent input to an appropriate pattern of spike output. Although Ca 2+ -activated K + channels are known to control spike frequency in central neurons, Ca 2+ -activated K + channels of intermediate conductance (KCa3.1) are believed to be restricted to peripheral neurons. We now report that cerebellar Purkinje cells express KCa3.1 channels, as evidenced through single-cell RT-PCR, immunocytochemistry, pharmacology, and single-channel recordings. Furthermore, KCa3.1 channels coimmunoprecipitate and interact with low voltage-activated Cav3.2 Ca 2+ channels at the nanodomain level to support a previously undescribed transient voltage-and Ca 2+ -dependent current. As a result, subthreshold parallel fiber excitatory postsynaptic potentials (EPSPs) activate Cav3 Ca 2+ influx to trigger a KCa3.1-mediated regulation of the EPSP and subsequent after-hyperpolarization. The Cav3-KCa3.1 complex provides powerful control over temporal summation of EPSPs, effectively suppressing low frequencies of parallel fiber input. KCa3.1 channels thus contribute to a high-pass filter that allows Purkinje cells to respond preferentially to high-frequency parallel fiber bursts characteristic of sensory input.C entral neurons receive an enormous number of spontaneously active synaptic inputs, but exhibit the capacity to differentiate features of sensory input from background noise. Cerebellar Purkinje cells are contacted by up to ∼150,000 parallel fibers from granule cells, of which only a subset will convey sensory information at any given time. The activation of a peripheral receptive field is transmitted to the cerebellar cortex by mossy fibers in the form of high-frequency spike bursts (1). The resulting temporal summation of excitatory postsynaptic potentials (EPSPs) generates a similar high-frequency burst in granule cells (2). Purkinje cells should then also possess the means to respond effectively to bursts of parallel fiber input that convey sensory information compared with background activity.Postsynaptic membrane excitability can be controlled by activation of K + channels. There are two established types of Ca 2+ -activated K + (KCa) channels in CNS neurons: small conductance (SK, KCa2.x) and big conductance (BK, KCa1.1) (3, 4). A third class of intermediate conductance (KCa3.1, SK4, IK1) KCa channel is thought to be expressed only in microglia and endothelial cells in the CNS (3, 5, 6). KCa3.1 channels are gated by calmodulin in a similar manner to KCa2.x channels but are insensitive to block by apamin and tetraethylammonium (TEA) (6-8). Instead, the KCa3.1 α-subunit, encoded by the gene KCNN4, has specific residues that bind charybdotoxin and 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) (5-7, 9, 10).In cerebellar Purkinje cells, KCa1.1 and KCa2.2 channels are activated during a spike by high voltage-activated (HVA) P-type Ca 2+ channels (11). In contrast, low voltage-activated (LVA) Cav3 (T-type) Ca 2+ channe...

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“…This is achieved through effective integration of correlated activity onto the PCs which must be able to act as coincidence detector. The precision of time spiking in PCs is strongly regulated by GABAergic synapses through feed-forward inhibition and because effective summation for spike generation of multiple asynchronous PFs inputs can occur within a time window of only a few milliseconds (Mittmann et al, 2005). Therefore, we explored the possibility that fear-related longterm plastic changes may affect this time window and thereby influence the output of the whole neuronal network.…”

Section: Neural Basis Of the Cerebellar Involvement In Learned Fearmentioning

confidence: 99%

“…In several brain structures it has been shown that precisely timed signal processing depends on direct monosynaptic excitation and underlying disynaptic inhibition (feed-forward inhibition) (Pouille andScanziani 2001 andMittmann et al 2005). All theories of timing concerning the cerebellum require that the output of the cerebellar cortex, encoded in the axons of PCs, be precisely tuned in response to sensory stimulation.…”

Section: Neural Basis Of the Cerebellar Involvement In Learned Fearmentioning

confidence: 99%

Cerebellum and emotional behavior

Sacchetti¹,

Scelfo²,

Strata³

2009

Neuroscience

129

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Fear conditioning involves learning that a previously neutral stimulus (CS) predicts an aversive unconditioned stimulus (US). Lesions of the cerebellar vermis may affect fear memory without altering baseline motor/autonomic responses to the frightening stimuli. Reversible inactivation of the vermis during the consolidation period impairs retention of fear memory. In patients with medial cerebellar lesions conditioned bradycardia is impaired. In humans, cerebellar areas around the vermis are activated during mental recall of emotional personal episodes, if a loved partner receives a pain stimulus, and during learning of a CS-US association. Moreover, patients with cerebellar stroke may fail to show overt emotional changes. In such patients, however, the activity of several areas, including ventromedial prefrontal cortex, anterior cingulate, pulvinar and insular cortex, is significantly increased relative to healthy subjects when exposed to frightening stimuli. Therefore, other structures may serve to maintain fear response after cerebellar damage. These data indicate that the vermis is involved in the formation of fear memory traces. We suggest that the vermis is not only involved in regulating the autonomic/motor responses, but that it also participates in forming new CS-US associations thus eliciting appropriate responses to new stimuli or situations. In other words, the cerebellum may translate an emotional state elaborated elsewhere into autonomic and motor responses.

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Feed‐forward inhibition shapes the spike output of cerebellar Purkinje cells

Cited by 288 publications

References 45 publications

Interneurons of the cerebellar cortex toggle Purkinje cells between up and down states

Interneurons of the cerebellar cortex toggle Purkinje cells between up and down states

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

Cerebellum and emotional behavior

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