Absence Of Synaptic Transmission Research Articles

Optical recording of oscillatory activity in the absence of external Ca2+ in the embryonic chick olfactory bulb

We applied 464/1020-site optical recording systems with a voltage-sensitive dye (NK2761) to the embryonic chick olfactory system and detected oscillatory activity in the olfactory bulb (OB) in the absence of synaptic transmission. In embryonic day 8–10 (E8-E10) chick olfactory nerve (N.I)-OB-forebrain preparations, the removal of Ca2+ from the external solution completely blocked the glutamatergic excitatory postsynaptic potential (EPSP) from the N.I to the OB as well as oscillations following the EPSP. However, a novel type of oscillatory activity was detected in the OB with the long-term perfusion of a Ca2+-free solution. The characteristics of oscillatory activity in the Ca2+-free solution differed from those in normal physiological solution. The present results suggest the existence of a neural communication system in the absence of synaptic transmission at the early stage of embryonic development.

The mechanisms shaping CA2 pyramidal neuron action potential bursting induced by muscarinic acetylcholine receptor activation.

Recent studies have revealed that hippocampal area CA2 plays an important role in hippocampal network function. Disruption of this region has been implicated in neuropsychiatric disorders. It is well appreciated that cholinergic input to the hippocampus plays an important role in learning and memory. While the effect of elevated cholinergic tone has been well studied in areas CA1 and CA3, it remains unclear how changes in cholinergic tone impact synaptic transmission and the intrinsic properties of neurons in area CA2. In this study, we applied the cholinergic agonist carbachol and performed on-cell, whole-cell, and extracellular recordings in area CA2. We observed that under conditions of high cholinergic tone, CA2 pyramidal neurons depolarized and rhythmically fired bursts of action potentials. This depolarization depended on the activation of M1 and M3 cholinergic receptors. Furthermore, we examined how the intrinsic properties and action-potential firing were altered in CA2 pyramidal neurons treated with 10 µM carbachol. While this intrinsic burst firing persisted in the absence of synaptic transmission, bursts were shaped by synaptic inputs in the intact network. We found that both excitatory and inhibitory synaptic transmission were reduced upon carbachol treatment. Finally, we examined the contribution of different channels to the cholinergic-induced changes in neuronal properties. We found that a conductance from Kv7 channels partially contributed to carbachol-induced changes in resting membrane potential and membrane resistance. We also found that D-type potassium currents contributed to controlling several properties of the bursts, including firing rate and burst kinetics. Furthermore, we determined that T-type calcium channels and small conductance calcium-activated potassium channels play a role in regulating bursting activity.

Frequency-dependent entrainment of spontaneous Ca transients in the dendritic tufts of CA1 pyramidal cells in rat hippocampal slice preparations by weak AC electric field

Neurons in the central nervous systems are exposed to endogenous oscillating electric fields and their activities are likely to be modified by those fields. We had previously investigated the effects of AC electric field by using a newly developed method to monitor local Ca transients in the dendrites of a neuronal population in acute rat hippocampal slices and reported that spontaneously occurring Ca transients in the tufts of the apical dendrites of CA1 pyramidal neurons become entrained to subthreshold AC electric fields. To further our understanding of the impact of AC fields on dendritic activities, in the present study we examined three questions: how does the extent of entrainment depend on the frequency of the applied field, how does the mean phase of the dendritic activities during field application depend on the frequency of the field, and whether the entrainment can be seen in the absence of synaptic transmission. We have found that, the extent of entrainment is significantly greater at a low frequency band (1–4 Hz) compared to a high frequency band (8–16 Hz), 0.688 ± 0.027 at 2 Hz compared to 0.087 ± 0.016 at 16 Hz in case of 7 mV/mm field strength, that the entrainment can be observed when synaptic transmission is pharmacologically blocked, and that the mean phase of the Ca transients during field stimulation at a low frequency band (1–4 Hz) stays constant. These results indicate that the electric fields with physiologically feasible frequencies and intensities can entrain activities of the dendrites in a frequency-dependent manner independent of synaptic transmission. AC electric fields during oscillatory brain activities might play a role in synchronizing neural activities by modulating dendritic activities.

Self-propagating, non-synaptic epileptiform activity recruits neurons by endogenous electric fields

It is well documented that synapses play a significant role in the transmission of information between neurons. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Previous studies have shown that propagation of epileptiform activity takes place in the absence of synaptic transmission and gap junctions and is outside the range of ionic diffusion and axonal conduction. Computer simulations indicate that electric field coupling could be responsible for the propagation of neural activity under pathological conditions such as epilepsy. Electric fields can modulate neuronal membrane voltage, but there is no experimental evidence suggesting that electric field coupling can mediate self-regenerating propagation of neural activity. Here we examine the role of electric field coupling by eliminating all forms of neural communications except electric field coupling with a cut through the neural tissue. We show that 4-AP induced activity generates an electric field capable of recruiting neurons on the distal side of the cut. Experiments also show that applied electric fields with amplitudes similar to endogenous values can induce propagating waves. Finally, we show that canceling the electrical field at a given point can block spontaneous propagation. The results from these in vitro electrophysiology experiments suggest that electric field coupling is a critical mechanism for non-synaptic neural propagation and therefore could contribute to the propagation of epileptic activity in the brain.

Abstract #110: Ephaptic coupling, a mechanism for spontaneous neural propagation in the brain

It is well documented that synapses play a significant role in the transmission of information between neurons in the brain. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Several experimental results have shown that propagation of epileptiform activity in rodent hippocampi propagates at a speed of ∼0.1 m/s. This observed activity in the 4-AP model propagates independently of synaptic transmission and gap junctions, and is outside the range of ionic diffusion and axonal conduction speeds. Compartment modeling of pyramidal neurons indicate that ephaptic coupling, or endogenous electric fields, could be responsible for this propagation of neural activity in pathological conditions such as epilepsy. Recent studies suggest electric fields can activate neighboring neurons, thereby generating a self-propagating wave. However, there is no experimental data suggesting ephaptic coupling is necessary and sufficient for spontaneous, self-regenerating propagation of neural activity. Using in vitro and in vivo electrophysiology in combination with imaging of trans-membrane voltages using genetically encoded voltage indicators, we test the hypothesis that ephaptic coupling is a critical mechanism for non-synaptic neural propagation. We have developed a novel extracellular electric field clamp capable of measuring the endogenous field and generate an "anti" field to block non-synaptic spontaneous propagation in the rodent hippocampus (Figure 1A). By blocking propagation, we are able to show that ephaptic coupling is a necessary mechanism for propagation of spontaneous activity. Finally, since electric fields propagate as volume conductors, we test if activity can propagate through a complete physical cut of the tissue, thereby eliminating all other forms of close cell-to-cell communication and showing that electric fields alone are sufficient to mediate non-synaptic propagation. Preliminary results suggest that spontaneous epileptiform activity propagates by triggering the activity on the other side across the cut with ephaptic coupling without changing the speed (Figure 1B). Our findings suggest that ephaptic coupling is necessary and sufficient to mediate non-synaptic neural propagation. Further investigation of this mechanism could explain how focal seizures appear to start abruptly and unpredictably, and how the rare micro-seizures of human partial epilepsy (seizure-like events that are not clinically detectable and are resistant to most common antiepileptic drugs) propagate through the hippocampus and cortex. Furthermore, endogenous electric fields could play an important role in brain function and could provide an explanation for unresolved mechanisms of deep brain stimulation or transcranial direct current stimulation (tDCS).

Solitonic conduction of electrotonic signals in neuronal branchlets with polarized microstructure

A model of solitonic conduction in neuronal branchlets with microstructure is presented. The application of cable theory to neurons with microstructure results in a nonlinear cable equation that is solved using a direct method to obtain analytical approximations of traveling wave solutions. It is shown that a linear superposition of two oppositely directed traveling waves demonstrate solitonic interaction: colliding waves can penetrate through each other, and continue fully intact as the exact pulses that entered the collision. These findings indicate that microstructure when polarized can sustain solitary waves that propagate at a constant velocity without attenuation or distortion in the absence of synaptic transmission. Solitonic conduction in a neuronal branchlet arising from polarizability of its microstructure is a novel signaling mode of electrotonic signals in thin processes (<0.5 μm diameter).

Slow Bursting Neurons of Mouse Cortical Layer 6b Are Depolarized by Hypocretin/Orexin and Major Transmitters of Arousal.

Neurons firing spontaneously in bursts in the absence of synaptic transmission have been previously recorded in different layers of cortical brain slices. It has been suggested that such neurons could contribute to the generation of alternating UP and DOWN states, a pattern of activity seen during slow-wave sleep. Here, we show that in layer 6b (L6b), known from our previous studies to contain neurons highly responsive to the wake-promoting transmitter hypocretin/orexin (hcrt/orx), there is a set of neurons, endowed with distinct intrinsic properties, which displayed a strong propensity to fire spontaneously in rhythmic bursts. In response to small depolarizing steps, they responded with a delayed firing of action potentials which, upon higher depolarizing steps, invariably inactivated and were followed by a depolarized plateau potential and a depolarizing afterpotential. These cells also displayed a strong hyperpolarization-activated rectification compatible with the presence of an Ih current. Most L6b neurons with such properties were able to fire spontaneously in bursts. Their bursting activity was of intrinsic origin as it persisted not only in presence of blockers of ionotropic glutamatergic and GABAergic receptors but also in a condition of complete synaptic blockade. However, a small number of these neurons displayed a mix of intrinsic bursting and synaptically driven recurrent UP and DOWN states. Most of the bursting L6b neurons were depolarized and excited by hcrt/orx through a direct postsynaptic mechanism that led to tonic firing and eventually inactivation. Similarly, they were directly excited by noradrenaline, histamine, dopamine, and neurotensin. Finally, the intracellular injection of these cells with dye and their subsequent Neurolucida reconstruction indicated that they were spiny non-pyramidal neurons. These results lead us to suggest that the propensity for slow rhythmic bursting of this set of L6b neurons could be directly impeded by hcrt/orx and other wake-promoting transmitters.

Contrasting responses within a single neuron class enable sex-specific attraction in Caenorhabditis elegans

Animals find mates and food, and avoid predators, by navigating to regions within a favorable range of available sensory cues. How are these ranges set and recognized? Here we show that male Caenorhabditis elegans exhibit strong concentration preferences for sex-specific small molecule cues secreted by hermaphrodites, and that these preferences emerge from the collective dynamics of a single male-specific class of neurons, the cephalic sensory neurons (CEMs). Within a single worm, CEM responses are dissimilar, not determined by anatomical classification and can be excitatory or inhibitory. Response kinetics vary by concentration, suggesting a mechanism for establishing preferences. CEM responses are enhanced in the absence of synaptic transmission, and worms with only one intact CEM show nonpreferential attraction to all concentrations of ascaroside for which CEM is the primary sensor, suggesting that synaptic modulation of CEM responses is necessary for establishing preferences. A heterogeneous concentration-dependent sensory representation thus appears to allow a single neural class to set behavioral preferences and recognize ranges of sensory cues.

Glycine transporter-1 controls nonsynaptic inhibitory actions of glycine receptors in the neonatal rat hippocampus.

Although functional glycinergic synapses have not been identified in the hippocampus, neurons in this area express Cl(-) permeable extrasynaptic glycine receptors (GlyRs). In experiments on CA3 pyramidal neurons on postnatal day 0-6 rat hippocampal slices, we detected robust GlyR activity as a tonic current and as single-channel events. Glycine release was independent of neuronal activity or extracellular Ca(2+). The endogenous GlyR activity was strongly enhanced by inhibition of the glycine-transporter-1 (GlyT1). Blockade of GlyT1 also caused a profound increase in the baseline current induced by exogenous glycine. Inhibition of GlyT1 reduced the frequency of spontaneous network events known as field giant depolarizing potentials (fGDPs) and of the unit activity in the absence of synaptic transmission. This inhibitory action on fGDPs was mimicked by applying 2 μm glycine or 0.1 μm isoguvacine, a GABAA-receptor agonist. Furthermore, 2 μm glycine suppressed unit spiking in the absence of synaptic transmission. Hence, despite the well known depolarizing Cl(-) equilibrium potential of neonatal hippocampal neurons, physiologically relevant extracellular glycine concentrations can exert an inhibitory action. The present data show that, akin to GABA uptake, GlyT1 exerts a powerful modulatory action on network events in the newborn hippocampus.

The neuromuscular junction: Selective remodeling of synaptic regulators at the nerve/muscle interface

The peripheral synapses between motoneurons and skeletal muscle fibers, the neuromuscular junctions, are ideal to investigate the general principles of synaptogenesis that depend on the interaction of activity-dependent and activity-independent signals. Much has been learned from gene “knock out” mouse models that helped to identify major synaptic regulators. The “knock out” approach, however, may not distinguish between changes arising from the disruption of molecular signaling pathways and changes caused by the absence of synaptic transmission. To circumvent these problems, postsynaptic activity was modulated in mouse models by specifically targeting endplate receptors or the activity of synaptic regulators such as MuSK. Both regulators have multiple functions and acetylcholine receptors are not just signal transducers but regulate the localization and architecture of endplates. The results show that detailed analysis of mouse models will help to understand the complexity in mechanisms that regulate synaptic remodeling.

GABA release by hippocampal astrocytes

Astrocytes can directly influence neuronal activity through the release of various transmitters acting on membrane receptors expressed by neurons. However, in contrast to glutamate and ATP for instance, the release of GABA (γ-amino-butyric acid) by astrocytes is still poorly documented. Here, we used whole-cell recordings in rat acute brain slices and electron microscopy to test whether hippocampal astrocytes release the inhibitory transmitter GABA. We observed that slow transient inhibitory currents due to the activation of GABAA receptors occur spontaneously in principal neurons of the three main hippocampal fields (CA1, CA3, and dentate gyrus). These currents share characteristics with the slow NMDA receptor-mediated currents previously shown to result from astrocytic glutamate release: they occur in the absence of synaptic transmission and have variable kinetics and amplitudes as well as low frequencies. Osmotic pressure reduction, known to enhance transmitter release from astrocytes, similarly increased the frequency of non-synaptic GABA and glutamate currents. Simultaneous occurrence of slow inhibitory and excitatory currents was extremely rare. Yet, electron microscopy examination of immunostained hippocampal sections shows that about 80% of hippocampal astrocytes [positive for glial fibrillary acidic protein (GFAP)] were immunostained for GABA. Our results provide quantitative characteristics of the astrocyte-to-neuron GABAergic signaling. They also suggest that all principal neurons of the hippocampal network are under a dual, excitatory and inhibitory, influence of astrocytes. The relevance of the astrocytic release of GABA, and glutamate, on the physiopathology of the hippocampus remains to be established.

High-Frequency Network Activity, Global Increase in Neuronal Activity, and Synchrony Expansion Precede Epileptic SeizuresIn Vitro

How seizures start is a major question in epilepsy research. Preictal EEG changes occur in both human patients and animal models, but their underlying mechanisms and relationship with seizure initiation remain unknown. Here we demonstrate the existence, in the hippocampal CA1 region, of a preictal state characterized by the progressive and global increase in neuronal activity associated with a widespread buildup of low-amplitude high-frequency activity (HFA) (>100 Hz) and reduction in system complexity. HFA is generated by the firing of neurons, mainly pyramidal cells, at much lower frequencies. Individual cycles of HFA are generated by the near-synchronous (within approximately 5 ms) firing of small numbers of pyramidal cells. The presence of HFA in the low-calcium model implicates nonsynaptic synchronization; the presence of very similar HFA in the high-potassium model shows that it does not depend on an absence of synaptic transmission. Immediately before seizure onset, CA1 is in a state of high sensitivity in which weak depolarizing or synchronizing perturbations can trigger seizures. Transition to seizure is characterized by a rapid expansion and fusion of the neuronal populations responsible for HFA, associated with a progressive slowing of HFA, leading to a single, massive, hypersynchronous cluster generating the high-amplitude low-frequency activity of the seizure.

Experience-Driven Axon Retraction in the Pharmacologically Inactivated Visual Cortex Does Not Require Synaptic Transmission

BackgroundExperience during early postnatal development plays an important role in the refinement of specific neural connections in the brain. In the mammalian visual system, altered visual experiences induce plastic adaptation of visual cortical responses and guide rearrangements of afferent axons from the lateral geniculate nucleus. Previous studies using visual deprivation demonstrated that the afferents serving an open eye significantly retract when cortical neurons are pharmacologically inhibited by applying a γ-aminobutyric acid type A receptor agonist, muscimol, whereas those serving a deprived eye are rescued from retraction, suggesting that presynaptic activity can lead to the retraction of geniculocortical axons in the absence of postsynaptic activity. Because muscimol application suppresses the spike activity of cortical neurons leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of active axons in the inhibited cortex.Method and FindingsNew studies reported here determined whether experience-driven axon retraction can occur in the visual cortex inactivated by blocking synaptic inputs. We inactivated the primary visual cortex of kittens by suppressing synaptic transmission with cortical injections of botulinum neurotoxin type E, which cleaves a synaptic protein, SNAP-25, and blocks transmitter release, and examined the geniculocortical axon morphology in the animals with normal vision and those deprived of vision binocularly. We found that afferent axons in the animals with normal vision showed a significant retraction in the inactivated cortex, as similarly observed in the muscimol-treated cortex, whereas the axons in the binocularly deprived animals were preserved.ConclusionsTherefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons.

Synchrony-asynchrony transitions in neuronal networks

Irregular spike timing over long durations or relative asynchronous spiking between cells is a ubiquitous phenomenon observed in many brain nuclei both in vivo and in vitro. Subthalamic neurons (STN) and globus pallidus (GP) neurons of the basal ganglia are good examples of such neuronal irregularity. They fire asynchronously normally, but become synchronous in Parkinson’s disease [1,2]. These cells have been shown to be autonomous, i.e., their oscillations are sustained in the absence of synaptic transmission. The prevalence of irregularity in such oscillatory neurons, and their tendency to become synchronous under disease conditions poses several challenges. They necessitate a detailed study of the interaction of oscillatory mechanisms that may contribute to synchronization between neurons with the sparsity of their interactions, the size of the network, and the external synaptic input. We study synchrony-asynchrony transitions in a model network of synaptically coupled STN or GP neurons with varying degrees of network size (N) and connectivity (number of presynaptic neurons per postsynaptic neuron, M <=N). We find the critical size (Ncrit) and critical number of connections (Mcrit for given N) needed in order to achieve global synchrony, as well as explore the nature and size of local cluster sates in the asynchronous state. The STN and GP neurons are modeled using Hodgkin-Huxley type of equations that incorporate sodium, potassium, calcium, a low-threshold calcium (T), and an afterhyperpolarization (AHP) activated potassium current [3]. In a network of two or more mutually excitatory neurons, for example, spike-to-spike synchrony can be achieved by increasing the coupling conductance beyond a critical level. In the unsynchronized regime, a phase drift between spike times of the neurons as well as multiple-frequency locked states can result. The level of mutual coupling required for synchrony in an all-to-all coupled network is found to increase as square root of N. In a sparsely connected network local cluster states emerge for weaker coupling, but spike-to-spike synchrony is also achieved for stronger coupling. Synchrony breaks down if the number of presynaptic neurons is fewer than a critical number. An external common synaptic inhibitory input given at Poisson intervals with a fixed arrival rate can cause asynchrony as well as enhance the frequency of the network at all network sizes.

Mechanisms underlying working memory for novel information

In this Opinion article we describe a theory that the brain mechanisms underlying working memory for novel information include a buffer in parahippocampal cortices. Computational modeling indicates that mechanisms for maintaining novel information in working memory could differ from mechanisms for maintaining familiar information. Electrophysiological data suggest that the buffer for novel information depends on acetylcholine. Acetylcholine activates single-cell mechanisms that underlie persistent spiking of neurons in the absence of synaptic transmission, allowing maintenance of information without prior synaptic modification. fMRI studies and lesion studies suggest that parahippocampal regions mediate working memory for novel stimuli, and the effects of cholinergic blockade impair this function. These intrinsic mechanisms in parahippocampal cortices provide an important alternative to theories of working memory based on recurrent synaptic excitation.

Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Bötzinger complex (preBötC) is the primary site of respiratory rhythm generation in the mammal

Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Bötzinger complex (preBötC) is the primary site of respiratory rhythm generation in the mammal

KCNQ/Kv7 Channel Regulation of Hippocampal Gamma-Frequency Firing in the Absence of Synaptic Transmission

Synchronous neuronal firing can be induced in hippocampal slices in the absence of synaptic transmission by lowering extracellular Ca2+ and raising extracellular K+. However, the ionic mechanisms underlying this nonsynaptic synchronous firing are not well understood. In this study we have investigated the role of KCNQ/Kv7 channels in regulating this form of nonsynaptic bursting activity. Incubation of rat hippocampal slices in reduced (<0.2 mM) [Ca2+]o and increased (6.3 mM) [K+]o, blocked synaptic transmission, increased neuronal firing, and led to the development of spontaneous periodic nonsynaptic epileptiform activity. This activity was recorded extracellularly as large (4.7 +/- 1.9 mV) depolarizing envelopes with superimposed high-frequency synchronous population spikes. These intraburst population spikes initially occurred at a high frequency (about 120 Hz), which decayed throughout the burst stabilizing in the gamma-frequency band (30-80 Hz). Further increasing [K+]o resulted in an increase in the interburst frequency without altering the intraburst population spike frequency. Application of retigabine (10 microM), a Kv7 channel modulator, completely abolished the bursts, in an XE-991-sensitive manner. Furthermore, application of the Kv7 channel blockers, linopirdine (10 microM) or XE-991 (10 microM) alone, abolished the gamma frequency, but not the higher-frequency population spike firing observed during low Ca2+/high K+ bursts. These data suggest that Kv7 channels are likely to play a role in the regulation of synchronous population firing activity.

Gap Junctions Between Accessory Medulla Neurons Appear to Synchronize Circadian Clock Cells of the CockroachLeucophaea maderae

The temporal organization of physiological and behavioral states is controlled by circadian clocks in apparently all eukaryotic organisms. In the cockroach Leucophaea maderae lesion and transplantation studies located the circadian pacemaker in the accessory medulla (AMe). The AMe is densely innervated by gamma-aminobutyric acid (GABA)-immunoreactive and peptidergic neurons, among them the pigment-dispersing factor immunoreactive circadian pacemaker candidates. The large majority of cells of the cockroach AMe spike regularly and synchronously in the gamma frequency range of 25-70 Hz as a result of synaptic and nonsynaptic coupling. Although GABAergic coupling forms assemblies of phase-locked cells, in the absence of synaptic release the cells remain synchronized but fire now at a stable phase difference. To determine whether these coupling mechanisms of AMe neurons, which are independent of synaptic release, are based on electrical synapses between the circadian pacemaker cells the gap-junction blockers halothane, octanol, and carbenoxolone were used in the presence and absence of synaptic transmission. Here, we show that different populations of AMe neurons appear to be coupled by gap junctions to maintain synchrony at a stable phase difference. This synchronization by gap junctions is a prerequisite to phase-locked assembly formation by synaptic interactions and to synchronous gamma-type action potential oscillations within the circadian clock.

Rhythmic Neuronal Discharge in the Medulla and Spinal Cord of Fetal Rats in the Absence of Synaptic Transmission

Spontaneous rhythmic neuronal activity is generated in the developing vertebrate nervous system. The patterned activity spreads diffusely throughout the fetal neuraxis. Here we demonstrate the ability of the fetal rat spinal cord and medulla to generate and transmit robust rhythmic patterns in the absence of synaptic activity. Regular rhythmic discharges were produced by fetal tissue bathed in low or zero [Ca(2+)](o) solution. The activity persisted in the presence of antagonists to neurotransmitter receptors that are known to mediate synaptic-mediated events associated with fetal rhythms. A combination of ventral root recordings and optical imaging using voltage-sensitive dyes demonstrated the extensive spread of rhythmic discharge in spinal cord and medullary neuronal populations of in vitro preparations. Whole cell recordings from medullary slices were performed to examine the ionic conductances and revealed the importance of persistent sodium conductances for generation of rhythmic activity in hypoglossal (XII) motoneurons. Rhythmic bursting in XII motoneurons persisted in the presence of gap junction blockers, although the amplitude of synchronized motor discharge recorded from nerve roots was diminished. We propose that nonsynaptically mediated conductances, potentially by extracellular ionic flux and/or ephaptic and electrotonic interactions mechanisms, act in concert with neurochemical transmission and gap junctions to promote the diffuse spread of rhythmic motor patterns in the developing nervous system.

Calcium-activated potassium channels are selectively coupled to P/Q-type calcium channels in cerebellar Purkinje neurons.

Cerebellar Purkinje neurons fire spontaneously in the absence of synaptic transmission. P/Q-type voltage-gated calcium channels and calcium-activated potassium channels are required for normal spontaneous activity. Blocking P/Q-type calcium channels paradoxically mimics the effects of blocking calcium-activated potassium channels. Thus, an important function of the P/Q-type calcium channels is to provide calcium for activation of calcium-activated potassium channels. Purkinje neurons express several classes of voltage-gated calcium channels, and the P/Q- and T-type channels make comparable contributions to total calcium entry after an action potential. Here we demonstrate that calcium-activated potassium channels are activated exclusively by calcium entering through P/Q-type voltage-gated calcium channels. This selective coupling is maintained even when calcium flux through voltage-gated channels is increased by increasing the extracellular calcium concentration. Small decreases in P/Q current density are likely to alter spontaneous activity of Purkinje neurons via decreased recruitment of calcium-activated potassium channels. In both human and murine animal models, mutations that decrease P/Q current density in Purkinje neurons also cause cerebellar ataxia. Alterations in the spontaneous activity of Purkinje neurons may be an important contributing factor to the ataxia in these subjects.