|Nelson Spruston (2009), Scholarpedia, 4(5):6130.||doi:10.4249/scholarpedia.6130||revision #130430 [link to/cite this article]|
Pyramidal neurons, also known as pyramidal cells, are neurons with a pyramidal shaped cell body (soma) and two distinct dendritic trees. The basal dendrites emerge from the base and the apical dendrites from the apex of the pyramidal cell body.
Pyramidal neurons have been observed in birds, fish, reptiles, and all mammals studied. They are found in forebrain structures such as the cerebral cortex, hippocampus, and amygdala, but not in the olfactory bulbs, striatum, midbrain, hindbrain, or spinal cord. They are the most numerous excitatory cell type in mammalian cortical structures, suggesting that they play important roles in advanced cognitive functions.
Pyramidal neurons were extensively characterized at the turn of the 19th century by the Spanish neuroscientist Santiago Ramon y Cajal. Since then, many other studies have probed the structure of pyramidal neurons in great detail. Like most neurons, pyramidal neurons have multiple dendrites and a single axon, but both dendrites and axons branch extensively. The dendrites of pyramidal neurons are usually regarded as input structures, receiving synaptic contacts from other neurons, while the axon serves as its output to other neurons. Pyramidal neuron dendrites can also release retrograde signaling molecules (e.g. endocannabinoids), so communication is somewhat bidirectional. The extensive branching of the dendrites and the axon allows a single to neuron to communicate with thousands of other neurons in a network.
Basal and apical dendrites
The structure of pyramidal neurons, although stereotypical, is quite variable, both between regions (e.g. hippocampus vs. neocortex) and within regions (e.g. layer II vs. layer V of neocortex). Nevertheless, pyramidal neurons have a stereotypical morphology, which is best characterized by the presence of separate basal and apical dendritic trees. Several basal dendrites emerge from the base of the pyramidal soma. Each basal dendrite branches up to several times before terminating. Viewed from below, the basal dendritic tree appears very similar in form to a stellate neuron (Elston and Rosa, 1998). A single apical dendrite emerges from the apex of the pyramidal soma. In most cases the primary apical dendrite extends for several hundred microns before branching to form an apical tuft, consisting of dendrites that branch a few times before terminating. In some cases the primary apical dendrite bifurcates to form two main apical dendrites. Emanating from the primary apical dendrites are several oblique branches, which typically branch once or twice before terminating. In some cases the primary apical dendrite bifurcates closer to the soma, giving rise to twin apical dendrites, each giving rise to several oblique branches.
Dendrites range in diameter from a few microns at the largest (e.g. the primary apical dendrite), to less than half a micron at the smallest (e.g. terminal branches). The linear distance from the basal end to the apical end of the dendritic tree usually measures in the hundreds of microns (range: ~200 µm to over 1 mm). Because dendrites branch extensively, the total dendritic length of a single neuron (sum of all branch lengths) measures in centimeters.
The lone axon emerging from the base of the pyramidal soma often extends over even longer distances, typically measured in tens of centimeters (e.g. one side of the brain to the other). The axon also branches profusely, thus resulting in many centimeters of total length.
Both the basal and apical dendrites of pyramidal neurons are studded with dendritic spines. These structures serve as the postsynaptic structure at most excitatory synaptic inputs received by the dendritic tree. Some excitatory inputs, however, contact the dendritic shaft in between dendritic spines. Thus, the number of dendritic spines (typically tens of thousands) serves as a lower-limit estimate for the number of excitatory synapses contacting a single pyramidal neuron.
Pyramidal neurons receive synaptic inputs from tens of thousands of excitatory synapses and several thousand inhibitory synapses. Most of the excitatory inputs use glutamate as the neurotransmitter, while inhibitory inputs use GABA. In addition, a number of other modulatory synaptic inputs also innervate pyramidal neurons (see below).
Excitation and inhibition
Active excitatory inputs result in excitatory postsynaptic potentials (EPSPs) through activation of AMPA and NMDA type glutamate receptors. Inhibitory inputs result in inhibitory postsynaptic potentials (IPSPs) through activation of GABAA or GABAB receptors. GABAA receptors can also mediate shunting inhibition.
Excitatory and inhibitory inputs to pyramidal neurons are integrated in an ongoing manner to determine the output of the neuron, which is ultimately action potential firing in the axon. The integration of excitatory and inhibitory synaptic inputs is a complex process that depends on the magnitude and timing of the synaptic conductances as well as the spatial relationship between the activated synapses and the final integration zone in the axon.
One of the great puzzles of pyramidal neuron function is how synaptic inputs to different parts of the dendritic tree are integrated differently. For example, different presynaptic neurons give rise to synapses on the apical tuft while others contact more proximal apical dendrites. The functional significance of this arrangement is intensely investigated but not completely understood. Similarly, the functional differences between synaptic inputs to basal versus apical dendrites are poorly understood, as are the functional consequences of specific types of inhibitory neurons, which target different compartments of the pyramidal neuron (e.g. soma versus apical dendritic tuft).
Synaptic integration is perhaps the principal function of the pyramidal neuron that gives rise to its computational power. Much of this integration occurs in the dendrites, so it is sometimes referred to as dendritic integration (Häusser et al., 2000; Magee, 2000; Spruston et al. 2008; Spruston, 2008). In addition to being influenced by the strength and spatial location of the activated synapses, dendritic integration is influenced by voltage-gated ion channels, which are abundant in pyramidal neuron dendrites (Johnston et al., 1996). The voltage-gated Na+, Ca2+ and K+ channels in pyramidal neuron dendrites make the dendrites excitable, which means they are capable of nonlinear integration that includes a variety of types of dendritic action potentials.
One form of excitable dendritic response is the backpropagating action potential. Following its initiation in the axon, the action potential propagates into the dendrites of the pyramidal neuron, though with some decrement in amplitude as it propagates (Stuart et al., 1997). Another form of dendritic excitability is the dendritically initiated action potential, or dendritic spike. These spikes are mediated by a combination of voltage-gated Na+ and Ca2+ channels, as well as NMDA receptors. These events begin in the dendrites and propagate toward the axon and the soma. This forward propagation of dendritic spikes is unreliable, however, so dendritic spikes sometimes fail to evoke an action potential in the axon (Häusser et al. 2000; Spruston, 2008). There is now good evidence that dendritic spikes can be generated in individual dendritic branches. Although these spikes attenuate severely before reaching the soma, they may serve as the output of a dendritic branch (Polsky et al. 2004; Losonczy and Magee, 2006), as well as a signal for dendritic plasticity (Golding et al. 2002; Gordon et al. 2006; Kampa et al. 2007; Remy and Spruston, 2007; Losonczy et al. 2008).
Other types of voltage-gated channels that are abundant in the dendrites of most pyramidal neurons include A-type K+ channels and hyperpolarization-activated cation channel channels (also known as HCN channels). The expression of both of these channel types is highest in distal apical dendrites, thus imparting additional location-dependent properties to dendritic integration (Hoffman et al. 1997; Stuart and Spruston, 1998; Magee, 1998; Lorincz et al., 2002).
Dendritic coincidence detection
One theory of pyramidal neuron function posits that the neuron responds best to coincident activation of multiple dendritic compartments. For example layer V pyramidal neurons in the neocortex have been shown to respond with a burst of action potentials when distal and proximal inputs are activated simultaneously (Larkum et al., 1999). The mechanism of the burst activation is a dendritic spike – mediated largely by voltage-gated Ca2+ channels – that occurs in the apical dendrites when an EPSP is activated together with a backpropagating action potential.
Another form of dendritic coincidence detection occurs when separate excitatory inputs activate the tuft and more proximal regions of the apical dendrites in hippocampal pyramidal neurons (Jarsky et al. 2005). In this case the proximal input is weaker, but it facilitates forward propagation of the dendritic spike initiated by the strong input to the tuft. Several other forms of coincidence detection in pyramidal neurons have been reported (Spruston 2008).
Intrinsic firing properties
While the nature of the stimulus can determine the type of output generated by a pyramidal neuron (e.g. single spike vs. burst), the intrinsic neuronal excitability is another important determinant of how the neuron responds to an input. Typically, neurons are classified according to how they respond to current injection, which varies considerably from one type of pyramidal neuron to the next. Most pyramidal neurons respond to continuous depolarizing current injection with a train of spikes that exhibits spike-frequency adaptation (accommodation). Many pyramidal neurons respond with one or more bursts of action potentials. The nature of this response is largely determined by the types of voltage-gated ion channels expressed in the neuron, but the structure of the dendritic tree is also important (Mainen and Sejnowski, 1996).
Modulation of pyramidal neuron function
In addition to the excitatory and inhibitory synaptic inputs received by pyramidal neurons, a host of other neurotransmitters can modulate pyramidal neuron function. These include acetylcholine, dopamine, serotonin, and norepinephrine. Each of these neurotransmitters is released from presynaptic specializations on the axons of neurons originating in basal forebrain and midbrain nuclei. These nuclei are activated differentially during various behavioral states. For example, activation of these neurotransmitter systems is very different during sleep versus wakefulness. The transmitters act on specialized metabotropic receptors in pyramidal neurons (and other neurons), leading to activations of signal transduction pathways that result in modulation of intrinsic excitability as well as synaptic function.
In addition to these subcortical neuromodulatory systems, more local synapses can act on metabotropic glutamate and GABA receptors. In addition, a number of peptide neurotransmitters can modulate pyramidal neuron function.
One of the most intensely studied aspects of pyramidal neuron function is plasticity – the ability of a neuron to change its function. As early as Cajal, neuroscientists have suggested that the ability of neurons and their synaptic connections to change lies at the heart of learning and memory. Pyramidal neurons have been the subject of hundreds or even thousands of studies of neural plasticity.
One of the most widely studied forms of neural plasticity is activity-dependent synaptic plasticity. Although first discovered in non-pyramidal neurons (Bliss and Lomo, 1973), the notion that synaptic strength can change in response to repeated synaptic activation is now well established in pyramidal neurons from the neocortex and hippocampus. The first form of synaptic plasticity described was long-term potentiation (LTP) of synaptic strength in response to high-frequency synaptic activation. Later studies determined that low-frequency activation could lead to the converse: long-term depression (LTD) of synaptic transmission (Dudek and Bear, 1992).
More recently, considerable attention has been focused on a bidirectional form of plasticity called spike-timing dependent plasticity (STDP), which depends on the relative timing of activation of the presynaptic and postsynaptic neurons (Markram et al., 1997; Bi and Poo, 1998). STDP is a complex process affected not only by spike timing, but also by several other factors including spike frequency, synaptic strength and dendritic location of the synapses (Sjostrom et al., 2008).
Studies of synaptic plasticity in pyramidal neurons have focused on the induction mechanisms as well as the expression mechanisms. Although there appear to be many forms of LTP and LTD, induction of the most widely studied version requires postsynaptic depolarization and NMDA receptor activation, as well as the ensuing rise in intracellular Ca2+ concentration (Bliss and Collingridge, 1993). Some current research is focused on the contributions of backpropagating action potentials and dendritic spikes to provide the postsynaptic depolarization necessary for induction of LTP and LTD (Kampa et al., 2007).
Whether the expression mechanisms are presynaptic, postsynaptic, or both, has been intensely debated for decades with a vast literature resulting from many studies. The bulk of evidence suggests that at least one common form of LTP involves the addition of AMPA receptors at the activated synapses, but other mechanisms have been reported as well (Malinow and Malenka, 2002). In concert with these changes, dendritic spines and their associated synapses may enlarge as a result of actin-based motility (Kasai et al., 2003; Matus, 2005). In keeping with this, pyramidal neurons contain a subset of large, structurally specialized synapses, which may result from learning and LTP (Fig. 12; Geinisman, 2000).
In addition to synaptic plasticity, a variety of forms of non-synaptic plasticity have been reported (Zhang and Linden, 2003). These types of plasticity typically involve changes in the intrinsic excitability, which affects the action potential firing properties of the affected neurons. While these changes are often thought of as global changes affecting the response of the neuron to all synaptic inputs, there is now good evidence that such changes can occur more locally, such as in individual dendritic branches of pyramidal neurons (Frick et al., 2004; Losonczy et al. 2008).
The stereotypical dendritic architecture of pyramidal neurons suggests that their structure is preserved to carry out some basic computational function in the nervous system. On the other hand, pyramidal neurons in different brain regions exhibit considerable diversity in structure and function, suggesting that they have evolved to carry out variants of these computational functions. The ability to modulate pyramidal neuron function in response to behavioral state or as a long-term response to prior activation (possibly as a mechanism of learning) are no doubt crucial to proper functioning of the nervous system. The abundance of pyramidal neurons in cortical structures suggests further that their proper function is necessary for cognitive processing, and thus deficits in pyramidal neuron function are likely to lead to cognitive deficits such as those associated with diseases such as Alzheimer’s disease or schizophrenia.
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- Pyramidal Cell in Wikipedia
Neuron, Dendrite, Dendritic spines, Dendritic processing, Neuronal excitability, Bursting