Apical dendrite

Two types of dendrites present on pyramidal cells are apical and basal dendrites. Apical dendrites are the most distal along the ascending trunk, and reside in layer 1. These distal apical dendrites receive synaptic input from related cortical as well as globally modulatory subcortical projections. Basal dendrites include shorter radially distributed dendrites which receive input from local pyramidal cells and interneurons.^[4] Pyramidal neurons segregate their inputs using proximal and apical dendrites.^[5]

Apical dendrites are studied in many ways. In cellular analysis, the electrical properties of the dendrite are studied using stimulus responses. A single surface shock of the cerebral cortex induces a 10–20 ms negative potential, a manifestation of the summed excitatory post-synaptic potentials (EPSPs) evoked in the distal portions of the apical dendrite.^[6] This has been called the dendritic spike.

The hippocampus contains pyramidal neurons in three areas: CA1, CA2, and CA3.^[2] The pyramidal neurons of each area have different properties. However, in all areas, dendritic synthesis of proteins is necessary for late long-term potentials in the hippocampal neurons.^[7] Neurons throughout the limbic system are known to have "burst" properties. These cells undergo synchronous and paroxysmal depolarizations, firing short sequences of action potentials called bursts.^[2]

The stratum oriens is the location between layers containing basal dendrites.^[8] The stratum lucidum, stratum radiatum, and the stratum moleculare-lacunosum are layers of apical dendrites and are ordered from least distant to most distant from the soma of the neuron.^[8]

CA3 projects Schaffer collaterals to apical dendrites in CA1.^[5] Individual pyramidal cells in the CA3 region have burst properties due to high densities of calcium channels in their proximal dendrites.^[2] Depolarization of the membrane may also trigger these bursts. Calcium entry into the cell causes more prolonged depolarization and increased action potentials. Usually curtailed by the hyperpolarizing local inhibition (due to the excitatory collateral system), this can lead to gradual recruitment of CA3 neurons and result in synchronized burst discharges.^[2] After hyperpolarization by calcium-dependent potassium conductance is also used as a method of controlling these bursts.^[2]

Hippocampal CA3 pyramidal cells have complex dendritic arbors which receive a stratified pattern of synaptic input from a variety of sources, including:

1. the commissural/associational fibers from ipsi- and contra-lateral CA3 pyramidal neurons which synapse on both the basal and mid-apical dendrites in the stratum oriens and stratum radiatum ^[4]
2. the mossy fibers from the granule cells of the dentate gyrus which synapse on the most proximal apical region, the stratum lucidum^[4]
3. the preforant path fibers from the entorhinal cortical pyramidal cells which synapse in the region of the most distal apical dendrites, the stratum lacunosum-moleculare.^[4]

Distal apical dendrites extend upwards from the soma. The shorter proximal apical dendrites extend outward and below. Shape of majority of 2d section is approximately a cylinder with a pointed base for the apical arbor.^[4] The apical dendrites and basal dendrites possess a radial organization pattern as they extend from the soma.^[4] Proximal apical dendrites and basal dendrites have approximately the same density.^[4] Apical dendrites possess a larger average total dendritic length (6332 vs 5062 micrometres) and surface area (12629 vs 9404 square micrometres; neither includes spines).^[4] However, the number of terminal branches for both apical and basal dendrites appear to be similar.^[4] Distances between successive branch points are shorter for basal dendrites. The basal dendrite however has approximately 3 fold fewer endings per primary dendrite.^[4] This and the lower maximum branch order suggest lower complexity than apical dendritic trees.^[4] Basal dendrites have a shorter distance to the tips and a more restricted range than apical dendrites. Data suggests that proximal apical and basal dendrites are more compressed but offer a wider local range of activity than distal apical dendrites.^[4]

In CA3 neurons the inputs are stratified and run in bands parallel to the cell body layer.^[4] Dendritic attenuation of synaptic current is described by an exponential relationship. The closer to the body the dendrite, the higher the EPSP amplitude.^[4] Electrical measurements and predictions validate the cylinder cross-section model.^[4] In the CA3, the temporoammonic (TA), commissural (COM), associational (ASSOC), and mossy fiber (MF) afferents all make excitatory glutamatergic (Glu) synapses on pyramidal cell dendrites (both apical and basal).^[2]

Since fast signals occurring in the basilar and proximal apical dendrites are transferred to the soma with at least a 20–25% efficiency, synapses in these dendrites each contribute more to the neuronal activation than distal apical synapses.^[4] In contrast, only slow signals from the distal dendrites are efficiently transferred to the soma, suggesting a modulatory role on the resting potential of the cell.^[4] It is hypothesized in several studies that this could be accomplished by varying the overall frequency of synaptic activity in the distal apical dendrite.^[4] Since a constant barrage of synaptic activity would approximate a constant current injection, the overall level of synaptic activity in the distal apical dendrite could set the depolarization level of the entire neuron.^[4] When a more efficient proximal synaptic activity is superimposed upon a sub-threshold depolarization due to distal activity, the cell has a high probability of firing an AP.^[4] In CA3, it is the perforant path projection from the entorhinal cortical cells that provides synaptic input to the most distal dendrites of the pyramidal cells. Assuming a frequency average of 7 spikes/sec, as few as five randomly firing entorhinal cortical cells would cause a steady level of depolarization in the distal dendrites of CA3b pyramidal cells.^[4] Amplitude and kinetics of the electrical signal vary as a function of position within the dendrite and signal frequency.^[4]

The major trigger for CA3 discharge is the afferent input from the dentate gyrus granule cells, from which mossy fiber terminals create very complex synapses on the proximal part of the CA3 apical dendrite in the stratum lucidum.^[2] Here they contact very complex dendritic spines. Glutamate release from single terminals evokes a large non-NMDA mediated EPSP.^[2] The most proximal regions of CA3 pyramidal dendrites receive mossy fiber input exclusively, mid-dendritic regions (strata radiatum on the apical side and the oriens on the basal side) receive principally associational and Commissural fibers (from other CA3 cells), and the distal apical dendrites (stratum lacunosum-moleculare) receive input from the temporoammonic afferents (from the entorhinal cortex).^[2] Mossy fiber input to CA3 exhibits different plasticity than that of typical long term potentiation because it is dependent on (or at least sensitive to) monoaminergic (see monoamine) activation of the cAMP 2nd messenger system.^[2]

These are similar to dentate cells. Interneuron cell types show unique dendritic arborization patterns and region specific targeting by axon collaterals.^[2] Investigators have shown that different morphologically defined interneurons show different electrical properties. These include both fast-spiking cells whose inhibitory post-synaptic potentials (IPSPs) sum to create small, smooth IPSPs in pyramidal cells and slow spiking cells (these produce large, fast-rising IPSPs in the pyramidal cell target). The dendritic region of CA3 is laminated.

For the input to the hippocampus proper, the temporoammonic pathway arises in layer III cells of the entorhinal cortex but separates from the perforant pathway to contact the most distal branches of the pyramidal cells in the stratum lacunosum-moleculare of CA1-CA3.^[2] The excitatory (glutaminergic) influence of this path has been questioned because influence on the pyramidal cells has been difficult to demonstrate.^[2] Recent experiments show that this modulation of pyramidal cells may differentially activate an interneuron subpopulation located in the distal reaches of the apical dendrites.^[2]

The study of inhibitory transmission is limited in the pyramidal neurons and their modulators because the large number of excitatory synapses has overshadowed physiological studies of the inhibitory neurons.^[9] The structure of inhibitory synapses on apical dendrites may not be as plastic as the excitatory synapses on these neurons.^[9] There is difficulty in differentiating the excitatory and inhibitory synapses using the electrophysiological recordings in many experiments.^[9] The excitatory synapses and their patterns are by comparison to the inhibitory system rather uniform in type and properties.^[9] The inhibitory system, by contrast, possess several (10) different types of synapses originating from specifically differentiated cells and are much more difficult to track.^[9] There is insufficient information to precisely distinguish between excitatory and inhibitory pathways contributing to the alterations in neurotransmitter expression and cell structure changes.^[9]

CA1 pyramidal cells make up a homogeneous population which together with relatives in subiculum comprise the primary output cells of the hippocampal formation.^[2] Primary excitatory inputs are via glutamatergic CA3 Schaffer collaterals (both ipsi- and contralateral), which contact dendritic spines on the apical and basal dendrites in strata radiatum and oriens.^[2] Additional excitatory input is via the temporoammonic system which synapses on distal apical dendrites in the stratum lacunosum-moleculare.^[2]

Imaging studies following localized changes intracellular calcium from discrete synaptic inputs have shown a role for these currents in synaptic plasticity.^[2] There is disagreement, however, as to how activity-dependent changes in synaptic inhibition might occur.^[2] Studies do agree that plasticity is enhanced when inhibition is reduced.^[2]

CA2 differs from other regions because it is one of the few areas to survive Temporal Lobe Epilepsy.^[2] Kainic acid, used to model TLE and related scleroses, affects primarily the mossy fiber synapses in CA3.^[2] It is thought that at these release glutamate with administration of KA.^[2] CA2 and CA3 can be distinguished using histological stains because the proximal apical dendrites of CA2 do not possess dendritic spines.^[8]

The entorhinal cortex (EC) is composed of six layers.^[2] Superficial layer I consists largely of afferent fibers onto the apical dendrites of the cells in layers II-VI. Caudal levels project strongly to rostral levels. Within each EC area, deeper layers innervate superficial layers, with superficial layers innervating adjacent superficial layers. Entorhinal pyramidal cells of layer V receive strong input from the perirhinal cortex and sensory cortices.^[2] These pyramidal cells then project into the superficial entorhinal layer II and III cells. Layer V EC cells have strong recurrent excitatory synapses much like CA3 layers in the hippocampus and when provoked are capable of burst activity. Medial to lateral entorhinal area connections are sparse and principally project from the medial EC to the lateral EC. These connections are not reciprocal.^[2] The majority of cells in the EC are pyramidal. More than 90% of layer V cells are regular spiking, with only a few burst-firing and fast-spiking cells.^[2] GABA is strong in superficial layers. Horizontal slice tissue preparations of both EC and hippocampus tissues show that exposure to low magnesium ion concentrations produces protracted seizure events. This response is likely a result of the interconnections of layer V pyramidal cells. Increases in extracellular potassium in seizures are seen in deeper layers. These responses are accurate reflections of in-vivo animal models.^[2]

In the piriform cortex, layer I consists mostly of afferent inputs to apical dendrites of deeper cells. Layer I is subdivided into layers Ia and Ib each having its own afferents. Layer II is densely packed with pyramidal and semilunar cells. Layer III contains mostly pyramidal cells in its superficial part.^[2]

In the piriform cortex the distal apical dendrites of layer III pyramidal neurons receive extrinsic inputs, which the corresponding proximal dendrites receive intrinsic inputs.^[5]

In each glomerulus the axons of the receptor neurons contact the apical dendrites of mitral cells, which are the principal projection neurons in the olfactory bulb. Cell bodies of mitral cells are located in a distinct layer deep in the olfactory glomeruli.^[10] Each mitral cell extends a primary dendrite to a single glomerulus, where the dendrite gives rise to an elaborate tuft of branches onto which the primary olfactory axons synapse.^[10] Each glomerulus in the mouse model, for example, contains approximately 25 mitral cells which receive innervation from approximately 25,000 olfactory receptor axons.^[10] The convergence increases the sensitivity of mitral cells to odor detection.^[10]

The most superficial layer of the cortex is the molecular or plexiform layer.^[1] It has a dense network of tangentially oriented fibers and cells made of axons of martinotti cells and stellate cells, as well as apical dendrites of pyramidal cells.^[1] Apical dendrites from pyramidal cells in the external granular layer and more prominently the external pyramidal layer project into the molecular layer.^[1] There are also in the plexiform layer GABAergic synaptic connections between the apical dendrites of granular cells and the basal dendrites of the tufted cells and mitral cells.^[1]

Some of the apical dendrites from the pyramidal cells in the cerebral cortex may be up to 10μm in diameter.^[11] The apical dendrite of a large pyramidal neuron in the cerebral cortex may contain thousands of spines.^[11] Spines in the cerebral cortex vary in size by several orders of magnitude from one region to another. Smallest have a length of 0.2μm and a volume of about 0.04 cubic micrometres and the largest a length of 6.5μm and a volume of 2 cubic micrometres.^[11]

Pyramidal cells are the majority class of cells in the neocortex.^[2] They have high density of dendritic spines, prominent apical dendrites, and axons that project out of the cortex as well as locally within it.^[2] Soma for these appear in all layers except I.^[2] Spiny stellate cells are distinguished from pyramidal cells here by the absence of the apical dendrite and the fact that their axons also do not leave the cortex.^[2] These cells are thought to begin as pyramidal neurons and then retract their apical dendrites and axons.^[2]

A defining characteristic of Purkinje cells in the cerebellum is the apical dendrite.^[10]

Dendritic arbor formation for pyramidal neurons in the cortices occurs progressively beginning in late embryonic stages of development and extending well into post-natal periods.^[2] Many dendrites of pyramidal neurons in deep layers branch and form connections in layer IV, while some extend to more superficial layers. Pyramidal cell dendrites in layer III branch to form arbors in layer I. Thalamocortical afferents will make synaptic contact with dendrites in layer IV while myriad of other inputs will meet dendrites in layer I. The post-synaptic structure is driven in part by signals from incoming afferent fibers and through life there is plasticity in the synapses.^[2]

The formation of these arbors is regulated by the strength of local signals during development.^[3] Several patterns in activity control the development of the brain. Action potential changes in the retina, hippocampus, cortex, and spinal cord provide activity-based signals both to the active neurons and their post-synaptic target cells. Spontaneous activity originating within neuronal gap junctions, the cortex sub-plate, and sensory inputs are all involved in the cell signaling that regulates dendrite growth.^[3]

Useful models of dendritic arbor formation are the Xenopus tadpoles, which are transparent in early stages of larval development and allow for dye-labeled neurons to be repeatedly imaged in the intact animal over several weeks.^[3] It has been observed from this and other models that there are rapid dendritic branch additions and retractions which lengthen the overall dendrite and accumulate more branches. This mirrors the development of axonal branches (both have a lifetime of approximately 10min).^[3] This activity decreases as neurons mature. Signals including glutamate from axon branches may increase branch additions.^[3]

Within the Xenopus tadpole model, several signaling systems have been studied. For example, in optical tectal neurons, dendrite arbor growth occurs approximately at the onset of retinal input.^[3] Many on the caudal tectate have “silent” synapses which are modulated only by N-methyl-D-aspartate (NMDA) receptors. As neurons mature, alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptors are added, increasing synaptic transmission. Neuron and dendrite development are NMDA dependent.^[3] Rapidly growing dendrite arbors are more dynamic than slowly growing ones and dendrites themselves play an active role in their own development.^[3] It has been shown in studies that transport of HCN (hyperpolarization activated cyclic nucleotide) gated channel isoforms to dendritic fields of CA1 pyramidal neurons in the hippocampus occurs in an age-specific manner in the developing hippocampus.^[12]

Among the signals studied in this system is CaMKII a calcium/calmodulin-regulated serine/threonine kinase which is required for induction by not expression of long-term potentiation.^[3] CaMKII mRNA is targeted to dendrites and both protein synthesis and enzyme activity are increased by strong synaptic input.^[3] Expression in Xenopus indicates that it is associated with the transition to slowed arbor growth. This suggests that activity promotes the reduction of dendrite branch growth and retraction, stabilizing the arbor configuration.^[3] The following pattern emerges for this system:

1. Branches with NMDA-only receptors mature and recruit AMPARs, which stabilize the branches.^[3]
2. These stable branches then add new branches with NMDAR-only synapses which either stabilize through AMPARs or retract. AMPAR additions are present in adults and account for synaptic plasticity.^[3]
3. CaMKII strengthening of signals results from the selective trafficking of GluR1 AMPARs into synapses. In long term depression (LTD) the GluR subunits of AMPARs undergo endocytosis.^[3]

Temporal differences in signaling over the course of neuron maturation suggest that the most promising studies of arbor development and synaptogenesis in the future are going to occur in intact brain systems.^[3]

Another model studied in apical dendrite development is the rat. Injection of tetanus toxin into neonatal rats has shown that growth of apical dendrites occurs normally during signal deprivation while basal dendrite growth is restricted. This indicates that neural activity is critical to new dendrite formation.^[13]

However, animal models may be insufficient to elucidate the complexity of these systems. Pyramidal cells in CA1, for example, are 30 times as thick in humans as they are in rats.^[14] The entorhinal cortex is also subdivided into as few as 8 and as many as 27 sections in humans (depending on the system used), whereas there are only 2 in rats and 7 in monkeys.^[14] The connections of the dentate gyrus and entorhinal cortex are also more sophisticated in humans.^[14] In rats and cats, a very large reciprocal connection exists between the entorhinal cortex and the olfactory system.^[2] In primates this connection is absent and there are highly differentiated connections between the multimodal parasensory and paralimbic cortices and the EC which are not as evident in rats and cats.^[2] The increased size of the primate subiculum may proportionally enhance its effects on the entorhinal cortex.^[2]

Pyramidal cell dendritic arbor formation in the anterior cingulate cortex (layers 2/3) is more complex in males and, in contrast the orbital prefrontal regions, dendritic arborization is greater in females suggesting a fundamental difference in the prefrontal organization in males and females.^[15] In rats, for example, exposure to estrogen either exogenously or endogenously during proestrous leads to increases in CA1 spine densities.^[10][15] These differences may be due to the presence of gonadal hormones which have been demonstrated to influence cell structure in the hippocampus. Treatment with testosterone has been shown to affect cortical neuron structure.^[15]