Dendrites Of Cortical Pyramidal Neurons Research Articles

The L1 cell adhesion molecule constrains dendritic spine density in pyramidal neurons of the mouse cerebral cortex.

A novel function for the L1 cell adhesion molecule, which binds the actin adaptor protein Ankyrin was identified in constraining dendritic spine density on pyramidal neurons in the mouse neocortex. In an L1-null mouse mutant increased spine density was observed on apical but not basal dendrites of pyramidal neurons in diverse cortical areas (prefrontal cortex layer 2/3, motor cortex layer 5, visual cortex layer 4. The Ankyrin binding motif (FIGQY) in the L1 cytoplasmic domain was critical for spine regulation, as demonstrated by increased spine density and altered spine morphology in the prefrontal cortex of a mouse knock-in mutant (L1YH) harboring a tyrosine (Y) to histidine (H) mutation in the FIGQY motif, which disrupted L1-Ankyrin association. This mutation is a known variant in the human L1 syndrome of intellectual disability. L1 was localized by immunofluorescence staining to spine heads and dendrites of cortical pyramidal neurons. L1 coimmunoprecipitated with Ankyrin B (220 kDa isoform) from lysates of wild type but not L1YH forebrain. This study provides insight into the molecular mechanism of spine regulation and underscores the potential for this adhesion molecule to regulate cognitive and other L1-related functions that are abnormal in the L1 syndrome.

Dendritic Compartmentalization of Learning-Related Plasticity

The dendrites of cortical pyramidal neurons receive synaptic inputs from different pathways that are organised according to their laminar target. This architectural scheme provides cortical neurons with a spatial mechanism to separate information, which may support neural flexibility required during learning. Here, we investigated layer-specific plasticity of sensory encoding following learning by recording from two different dendritic compartments, tuft and basal dendrites, of layer 2/3 (L2/3) pyramidal neurons in the auditory cortex of mice. Following auditory fear conditioning, auditory-evoked Ca2+ responses were enhanced in tuft, but not basal, dendrites leading to increased somatic action potential output. This is in direct contrast to the long held (and debated) hypothesis that, despite extensive dendritic arbours, neurons function as a simple one-compartment model. Two computational models of varying complexity based on the experimental data illustrated that this learning-related increase of auditory responses in tuft dendrites can account for the changes in somatic output. Taken together, we illustrate that neurons do not function as a single compartment, and dendritic compartmentalisation of learning-related plasticity may act to increase the computational power of pyramidal neurons.Significance StatementThis study directly investigates whether information processing in neurons is compartmentalized within different dendritic regions. Our findings shed light on the learning-related changes that occur in dendritic compartments residing in different layers of the cortex (i.e. tuft and basal dendrites), illustrating that L2/3 pyramidal neurons are able to compartmentalize learning signals which leads to enhanced somatic output. The compartmentalization of experience-dependent plasticity supports flexible sensory processing and may increase the computational power of single pyramidal neurons. In addition, it highlights the special role of tuft dendrites, the target of top-down inputs, in modulating sensory encoding following fear learning.

Frequency- and spike-timing-dependent mitochondrial Ca2+ signaling regulates the metabolic rate and synaptic efficacy in cortical neurons.

Mitochondrial activity is crucial for the plasticity of central synapses, but how the firing pattern of pre- and postsynaptic neurons affects the mitochondria remains elusive. We recorded changes in the fluorescence of cytosolic and mitochondrial Ca2+ indicators in cell bodies, axons, and dendrites of cortical pyramidal neurons in mouse brain slices while evoking pre- and postsynaptic spikes. Postsynaptic spike firing elicited fast mitochondrial Ca2+ responses that were about threefold larger in the somas and apical dendrites than in basal dendrites and axons. The amplitude of these responses and metabolic activity were extremely sensitive to the firing frequency. Furthermore, while an EPSP alone caused no detectable Ca2+ elevation in the dendritic mitochondria, the coincidence of EPSP with a backpropagating spike produced prominent, highly localized mitochondrial Ca2+ hotspots. Our results indicate that mitochondria decode the spike firing frequency and the Hebbian temporal coincidences into the Ca2+ signals, which are further translated into the metabolic output and most probably lead to long-term changes in synaptic efficacy.

Somatodendritic consistency check for temporal feature segmentation

The brain identifies potentially salient features within continuous information streams to process hierarchical temporal events. This requires the compression of information streams, for which effective computational principles are yet to be explored. Backpropagating action potentials can induce synaptic plasticity in the dendrites of cortical pyramidal neurons. By analogy with this effect, we model a self-supervising process that increases the similarity between dendritic and somatic activities where the somatic activity is normalized by a running average. We further show that a family of networks composed of the two-compartment neurons performs a surprisingly wide variety of complex unsupervised learning tasks, including chunking of temporal sequences and the source separation of mixed correlated signals. Common methods applicable to these temporal feature analyses were previously unknown. Our results suggest the powerful ability of neural networks with dendrites to analyze temporal features. This simple neuron model may also be potentially useful in neural engineering applications.

Unifying Long-Term Plasticity Rules for Excitatory Synapses by Modeling Dendrites of Cortical Pyramidal Neurons

SummaryA large number of experiments have indicated that precise spike times, firing rates, and synapse locations crucially determine the dynamics of long-term plasticity induction in excitatory synapses. However, it remains unknown how plasticity mechanisms of synapses distributed along dendritic trees cooperate to produce the wide spectrum of outcomes for various plasticity protocols. Here, we propose a four-pathway plasticity framework that is well grounded in experimental evidence and apply it to a biophysically realistic cortical pyramidal neuron model. We show in computer simulations that several seemingly contradictory experimental landmark studies are consistent with one unifying set of mechanisms when considering the effects of signal propagation in dendritic trees with respect to synapse location. Our model identifies specific spatiotemporal contributions of dendritic and axo-somatic spikes as well as of subthreshold activation of synaptic clusters, providing a unified parsimonious explanation not only for rate and timing dependence but also for location dependence of synaptic changes.

Paradoxical Excitatory Impact of SK Channels on Dendritic Excitability.

Dendritic excitability regulates how neurons integrate synaptic inputs and thereby influences neuronal output. As active dendritic events are associated with significant calcium influx they are likely to be modulated by calcium-dependent processes, such as calcium-activated potassium channels. Here we investigate the impact of small conductance calcium-activated potassium channels (SK channels) on dendritic excitability in male and female rat cortical pyramidal neurons in vitro and in vivo Using local applications of the SK channel antagonist apamin in vitro, we show that blocking somatic SK channels enhances action potential output, whereas blocking dendritic SK channels paradoxically reduces the generation of dendritic calcium spikes and associated somatic burst firing. Opposite effects were observed using the SK channel enhancer NS309. The effect of apamin on dendritic SK channels was occluded when R-type calcium channels were blocked, indicating that the inhibitory impact of apamin on dendritic calcium spikes involved R-type calcium channels. Comparable effects were observed in vivo Intracellular application of apamin via the somatic whole-cell recording pipette reduced the medium afterhyperpolarization and increased action potential output during UP states. In contrast, extracellular application of apamin to the cortical surface to block dendritic SK channels shifted the distribution of action potentials within UP states from an initial burst to a more distributed firing pattern, while having no impact on overall action potential firing frequency or UP and DOWN states. These data indicate that somatic and dendritic SK channels have opposite effects on neuronal excitability, with dendritic SK channels counter-intuitively promoting rather than suppressing neuronal output.SIGNIFICANCE STATEMENT Neurons typically receive input from other neurons onto processes called dendrites, and use electrical events such as action potentials for signaling. As electrical events in neurons are usually associated with calcium influx they can be regulated by calcium-dependent processes. One such process is through the activation of calcium-dependent potassium channels, which usually act to reduce action potential signaling. Although this is the case for calcium-dependent potassium channels found at the cell body, we show here that calcium-dependent potassium channels in dendrites of cortical pyramidal neurons counter-intuitively promote rather than suppress action potential output.

Probing Single Synapses via the Photolytic Release of Neurotransmitters.

The development of two-photon microscopy has revolutionized our understanding of how synapses are formed and how they transform synaptic inputs in dendritic spines—tiny protrusions that cover the dendrites of pyramidal neurons that receive most excitatory synaptic information in the brain. These discoveries have led us to better comprehend the neuronal computations that take place at the level of dendritic spines as well as within neuronal circuits with unprecedented resolution. Here, we describe a method that uses a two-photon (2P) microscope and 2P uncaging of caged neurotransmitters for the activation of single and multiple spines in the dendrites of cortical pyramidal neurons. In addition, we propose a cost-effective description of the components necessary for the construction of a one laser source-2P microscope capable of nearly simultaneous 2P uncaging of neurotransmitters and 2P calcium imaging of the activated spines and nearby dendrites. We provide a brief overview on how the use of these techniques have helped researchers in the last 15 years unravel the function of spines in: (a) information processing; (b) storage; and (c) integration of excitatory synaptic inputs.

De novo synaptogenesis induced by GABA in the developing mouse cortex.

Dendrites of cortical pyramidal neurons contain intermingled excitatory and inhibitory synapses. We studied the local mechanisms that regulate the formation and distribution of synapses. We found that local γ-aminobutyric acid (GABA) release on dendrites of mouse cortical layer 2/3 pyramidal neurons could induce gephyrin puncta and dendritic spine formation via GABA type A receptor activation and voltage-gated calcium channels during early postnatal development. Furthermore, the newly formed inhibitory and excitatory synaptic structures rapidly gained functions. Bidirectional manipulation of GABA release from somatostatin-positive interneurons increased and decreased the number of gephyrin puncta and dendritic spines, respectively. These results highlight a noncanonical function of GABA as a local synaptogenic element shaping the early establishment of neuronal circuitry in mouse cortex.

The role of microcircuits in the pre-frontal cortex in detecting and encoding temporally patterned information

Working memory is the capacity of the brain to hold information temporarily for immediate use. The neural correlate of this type of short-term memory is persistent spiking activity (PA) of both excitatory and inhibitory neurons, mainly in the pre-frontal cortex (PFC). Neurons embedded in PFC microcircuits integrate widespread information from various brain regions. PFC microcircuits of ~ten neurons are characterized by highly reciprocal connections and non-linear integration in their dendrites. Understanding how dendrites integrate information from multiple sources is crucial to explain their functional role. Spatial and temporal integration of signals occurs at dendrites before propagating to the soma, and plays a role in coding of information [1,2]. The main question is whether and how pyramidal neurons in such circuits can detect temporally structured information in order to timely adjust behavior. Dendrites of cortical pyramidal neurons have been shown to exhibit temporal sensitivity [1]. To address this question, we constructed a detailed PFC microcircuit, implemented in the NEURON simulation environment. We used reconstructed morphologies of layer 5 PFC pyramidal neurons, validated against experimental findings. The microcircuit consisted of nine pyramidal neurons and two interneurons, all interconnected [3]. To investigate temporal coding, we delivered temporally structured input to four out of the nine pyramidal neurons and assessed, given persistent activity emergence, a) the time-to-first-spike (ttfs) of each pyramidal cell and b) the Inter-Spike Intervals (ISIs) during PA. We find that temporally patterned inputs (simulated as different temporal orders of activated neurons) induce different responses, in both the ttfs and ISI distributions. To investigate the mechanisms that mediate this type of coding, we varied both the stimulus frequency and the pyramidal neuron morphologies in the microcircuit. We found that lower stimulus frequencies resulted in increased differences between various temporal orders of activation. The same result was observed when using neurons with morphologically complex dendritic trees, indicating that dendritic morphology may play a key role in the ability of PFC microcircuits to detect and encode temporally patterned inputs. Further, we investigated whether this type of temporal coding exhibits specificity, i.e. whether the PFC can consistently interpret similar temporally patterned inputs in a spectrum of background activity environments. Overall, this study seeks to understand at what level and how neuronal circuits implement the timely firing of PFC pyramidal neurons. Improving our understanding of temporal coding in complex areas like the PFC is essential for disentangling how the brain detects, encodes and transmits information. While dendrites of cortical neurons have been shown to detect differences in the order of incoming signals, our study breaks new ground in finding whether such a temporal code is preserved at the microcircuit level. These findings can be tested experimentally to further investigate the role of temporal coding in higher-level areas of the brain.

Branch specific and spike-order specific action potential invasion in basal, oblique, and apical dendrites of cortical pyramidal neurons.

In neocortical pyramidal neurons, action potentials (APs) propagate from the axon into the dendritic tree to influence distal synapses. Traditionally, AP backpropagation was studied in the thick apical trunk. Here, we used the principles of optical imaging developed by Cohen to investigate AP invasion into thin dendritic branches (basal, oblique, and tuft) of prefrontal cortical L5 pyramidal neurons. Multisite optical recordings from neighboring dendrites revealed a clear dichotomy between two seemingly equal dendritic branches belonging to the same cell ("sister branches"). We documented the variable efficacy of AP invasion in basal and oblique branches by revealing their AP voltage waveforms. Using fast multisite calcium imaging, we found that trains of APs are filtered differently between two apical tuft branches. Although one dendritic branch passes all spikes in an AP train, another branch belonging to the same neuron, same cortical layer, and same path distance from the cell body, experiences only one spike. Our data indicate that the vast differences in dendritic voltage and calcium transients, detected in dendrites of pyramidal neurons, arise from a nonuniform distribution of A-type [Formula: see text] conductance, an aggregate number of branch points in the path of the AP propagation and minute differences in dendritic diameter.

Location matters: somatic and dendritic SK channels answer to distinct calcium signals.

Voltage-dependent calcium channels (VDCCs) couple neuronal activity to diverse intracellular signals with exquisite spatiotemporal specificity. Using calcium imaging and electrophysiology, Jones and Stuart (J Neurosci 33: 19396-19405, 2013) examined the intimate relationship between distinct types of VDCCs and small-conductance calcium-activated potassium (SK) channels that contribute to the compartmentalized control of excitability in the soma and dendrites of cortical pyramidal neurons. Here we discuss the importance of calcium domains for signal specificity, explore the possible functions and mechanisms for local control of SK channels, and highlight technical considerations for the optical detection of calcium signals.

Different Calcium Sources Control Somatic versus Dendritic SK Channel Activation during Action Potentials

Small-conductance calcium-activated potassium (SK) channels play an important role in regulating neuronal excitability. While SK channels at the soma have long been known to contribute to the medium afterhyperpolarization (mAHP), recent evidence indicates they also regulate NMDA receptor activation in dendritic spines. Here we investigate the activation of SK channels in spines and dendrites of rat cortical pyramidal neurons during action potentials (APs), and compare this to SK channel activation at the soma. Using confocal calcium imaging, we demonstrate that the inhibition of SK channels with apamin results in a location-dependent increase in calcium influx into dendrites and spines during backpropagating APs (average increase, ~40%). This effect was occluded by block of R-type voltage-dependent calcium channels (VDCCs), but not by inhibition of N- or P/Q-type VDCCs, or block of calcium release from intracellular stores. During these experiments, we noticed that the calcium indicator (Oregon Green BAPTA-1) blocked the mAHP. Subsequent experiments using low concentrations of EGTA (1 mm) produced the same result, suggesting that somatic SK channels are not tightly colocalized with their calcium source. Consistent with this idea, all known subtypes of VDCCs except R-type were calcium sources for the apamin-sensitive mAHP at the soma. We conclude that SK channels in spines and dendrites of cortical pyramidal neurons regulate calcium influx during backpropagating APs in a distance-dependent manner, and are tightly coupled to R-type VDCCs. In contrast, SK channels activated by APs at the soma of these neurons are weakly coupled to a variety of VDCCs.

Ventral Medial Nucleus Neurons Send Thalamocortical Afferents More Widely and More Preferentially to Layer 1 than Neurons of the Ventral Anterior–Ventral Lateral Nuclear Complex in the Rat

Not only inhibitory afferent-dominant zone (IZ) of the ventral anterior-ventral lateral thalamic complex (VA-VL) but also the ventral medial nucleus (VM) is known to receive strong inputs from the basal ganglia and send axons to motor areas. We previously reported differences in axonal arborization between IZ neurons and the other VA-VL neurons in rats by single-neuron tracing with viral vectors. In the present study, the axonal arborization of single VM neurons was visualized by the same method, and compared with that of IZ neurons. VM neurons formed fewer axon collaterals in the striatum, but sent axon fibers more widely and more preferentially (79% of fibers) to layer 1 of cortical areas than IZ neurons. Furthermore, the VM seemed to contain at least 2 types of neurons; a major population of VM neurons sent axon fibers principally to motor-associated areas as VA-VL neurons did, and the other population projected mainly to orbital or cingulate areas. Although both VM and IZ neurons receive strong basal ganglia inputs, these results suggest that VM neurons, at a single neuron level, innervate the apical dendrites of cortical pyramidal neurons more intensely and more widely than IZ neurons.

Dopaminergic modulation of axonal potassium channels and action potential waveform in pyramidal neurons of prefrontal cortex

Voltage-gated K(+) (KV) channels play critical roles in shaping neuronal signals. KV channels distributed in the perisomatic regions and thick dendrites of cortical pyramidal neurons have been extensively studied. However, the properties and regulation of KV channels distributed in the thin axons remain unknown. In this study, by performing somatic and axonal patch-clamp recordings from layer 5 pyramidal neurons of prefrontal cortical slices, we showed that the rapidly inactivating A-currents mediated the transient K(+) currents evoked by action potential (AP) waveform command (KAP) at the soma, whereas the rapidly activating but slowly inactivating KV1-mediated D-currents dominated the KAP at the axon. In addition, activation of D1-like receptors for dopamine decreased the axonal K(+) currents, as a result of an increase in the activity of cAMP-PKA pathway. In contrast, activation of D2-like receptors showed an opposite effect on the axonal K(+) currents. Further experiments demonstrated that functional D1-like receptors were expressed at the main axon trunk and their activation could broaden the waveforms of axonal APs. Together, these results show that axonal KV channels were subjected to dopamine modulation, and this modulation could regulate the waveforms of propagating APs at the axon, suggesting an important role of dopaminergic modulation of axonal KV channels in regulating neuronal signalling.

Rapid dopaminergic and GABAergic modulation of calcium and voltage transients in dendrites of prefrontal cortex pyramidal neurons

The physiological responses of dendrites to dopaminergic inputs are poorly understood and controversial. We applied dopamine on one dendritic branch while simultaneously monitoring action potentials (APs) from multiple dendrites using either calcium-sensitive dye, voltage-sensitive dye or both. Dopaminergic suppression of dendritic calcium transients was rapid (<0.5 s) and restricted to the site of dopamine application. Voltage waveforms of backpropagating APs were minimally altered in the same dendrites where dopamine was confirmed to cause large suppression of calcium signals, as determined by dual voltage and calcium imaging. The dopamine effects on dendritic calcium transients were fully mimicked by D1 agonists, partially reduced by D1 antagonist and completely insensitive to protein kinase blockade; consistent with a membrane delimited mechanism. This dopamine effect was unaltered in the presence of L-, R- and T-type calcium channel blockers. The somatic excitability (i.e. AP firing) was not affected by strong dopaminergic stimulation of dendrites. Dopamine and GABA were then sequentially applied on the same dendrite. In contrast to dopamine, the pulses of GABA prohibited AP backpropagation distally from the application site, even in neurons with natural Cl− concentration (patch pipette removed). Thus, the neocortex employs at least two distinct mechanisms (dopamine and GABA) for rapid modulation of dendritic calcium influx. The spatio-temporal pattern of dendritic calcium suppression described in this paper is expected to occur during phasic dopaminergic signalling, when midbrain dopaminergic neurons generate a transient (0.5 s) burst of APs in response to a salient event.

Glutamate Spillover Promotes the Generation of NMDA Spikes

NMDA spikes are prominent in the basal dendrites of cortical pyramidal neurons and greatly expand their ability to integrate synaptic inputs. Calcium (Ca) signals during these spikes are important for synaptic plasticity and fundamentally depend on activation of NMDA receptors. However, the factors that shape the activation of these receptors and the initiation of NMDA spikes remain unclear. Here we examine the properties of NMDA spikes in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon imaging, we demonstrate that NMDA spikes evoke large Ca signals in both postsynaptic spines and nearby dendrites. We find that the dendrite Ca signals depend on NMDA and AMPA receptors but not sodium (Na) or Ca channels. Using voltage-clamp recordings, we show that activation of dendrite NMDA receptors is enhanced by concerted synaptic activity. Blocking glutamate reuptake further increases activation of these receptors and promotes the initiation of NMDA spikes. We conclude that glutamate spillover and recruitment of extrasynaptic receptors contribute to the initiation of NMDA spikes. These results have important implications for how synaptic activity generates both electrical and biochemical signals in dendrites and spines.

Receptor-like Protein-tyrosine Phosphatase α Enhances Cell Surface Expression of Neural Adhesion Molecule NB-3

Neural adhesion molecule NB-3 plays an important role in the apical dendrite development of layer V pyramidal neurons in the visual cortex, and receptor-like protein-tyrosine phosphatase α (PTPα) mediates NB-3 signaling in this process. Here we investigated the role of PTPα in regulating cell surface expression of NB-3. We found that cortical neurons from PTPα knock-out mice exhibited a lower level of NB-3 at the cell surface. When expressed in COS1 cells, NB-3 was enriched in the Golgi apparatus with a low level of cell surface expression. However, co-expression of PTPα increased the cell surface distribution of NB-3. Further analysis showed that PTPα facilitated Golgi exit of NB-3 and stabilized NB-3 protein at the cell surface by preventing its release from the plasma membrane. The extracellular region of PTPα but not its catalytic activity is necessary for its effect on NB-3 expression. Thus, the PTPα-mediated increase of NB-3 level at the cell surface represents a novel function of PTPα in NB-3 signaling in neural development.

GABABReceptor Modulation of Voltage-Sensitive Calcium Channels in Spines and Dendrites

Although primarily studied at the cell body, GABA(B) receptors (GABA(B)Rs) are abundant at spines and dendrites of cortical pyramidal neurons, where they are positioned to influence both synaptic and dendritic function. Here, we examine how GABA(B)Rs modulate calcium (Ca) signals evoked by action potentials (APs) in spines and dendrites of layer 2/3 pyramidal neurons in mouse prefrontal cortex. We first use two-photon microscopy to show that GABA(B)Rs inhibit AP Ca signals throughout the entire dendritic arbor of these neurons. We then use local pharmacology and GABA uncaging to show that dendritic GABA(B)Rs also decrease the input resistance, shorten the AP afterdepolarization, and generate inhibitory postsynaptic potentials. However, we find that these electrophysiological effects recorded at the cell body do not correlate with the inhibition of AP Ca signals measured in spines and dendrites. Instead, we use voltage-clamp recordings to show that GABA(B)Rs directly inhibit several subtypes of voltage-sensitive calcium channels (VSCCs) in both spines and dendrites. Given the importance of VSCC-mediated Ca signals for neuronal function, our results have implications for the functional role of dendritic GABA(B)Rs in the prefrontal cortex and throughout the brain.

Synaptic Integration Gradients in Single Cortical Pyramidal Cell Dendrites

Cortical pyramidal neurons receive thousands of synaptic inputs arriving at different dendritic locations with varying degrees of temporal synchrony. It is not known if different locations along single cortical dendrites integrate excitatory inputs in different ways. Here we have used two-photon glutamate uncaging and compartmental modeling to reveal a gradient of nonlinear synaptic integration in basal and apical oblique dendrites of cortical pyramidal neurons. Excitatory inputs to the proximal dendrite sum linearly and require precise temporal coincidence for effective summation, whereas distal inputs are amplified with high gain and integrated over broader time windows. This allows distal inputs to overcome their electrotonic disadvantage, and become surprisingly more effective than proximal inputs at influencing action potential output. Thus, single dendritic branches can already exhibit nonuniform synaptic integration, with the computational strategy shifting from temporal coding to rate coding along the dendrite.

Formation of Heteromeric Kv2 Channels in Mammalian Brain Neurons

The formation of heteromeric tetramers is a common feature of voltage-gated potassium (Kv) channels. This results in the generation of a variety of tetrameric Kv channels that exhibit distinct biophysical and biochemical characteristics. Kv2 delayed rectifier channels are, however, unique exceptions. It has been previously shown that mammalian Kv2.1 and Kv2.2 are localized in distinct domains of neuronal membranes and are not capable of forming heteromeric channels with each other (Hwang, P. M., Glatt, C. E., Bredt, D. S., Yellen, G., and Snyder, S. H. (1992) Neuron 8, 473-481). In this study, we report a novel form of rat Kv2.2, Kv2.2(long), which has not been previously recognized. Our data indicate that Kv2.2(long) is the predominant form of Kv2.2 expressed in cortical pyramidal neurons. In contrast to the previous findings, we also found that rat Kv2.1 and Kv2.2(long) are colocalized in the somata and proximal dendrites of cortical pyramidal neurons and are capable of forming functional heteromeric delayed rectifier channels. Our results suggest that the delayed rectifier currents, which regulate action potential firing, are encoded by heteromeric Kv2 channels in cortical neurons.