Nelson Spruston

Pyramidal neurons: dendritic structure and synaptic integration

Pyramidal neurons are characterized by their distinct apical and basal dendritic trees and the pyramidal shape of their soma. They are found in several regions of the CNS and, although the reasons for their abundance remain unclear, functional studies — especially of CA1 hippocampal and layer V neocortical pyramidal neurons — have offered insights into the functions of their unique cellular architecture. Pyramidal neurons are not all identical, but some shared functional principles can be identified. In particular, the existence of dendritic domains with distinct synaptic inputs, excitability, modulation and plasticity appears to be a common feature that allows synapses throughout the dendritic tree to contribute to action-potential generation. These properties support a variety of coincidence-detection mechanisms, which are likely to be crucial for synaptic integration and plasticity.

Action potential initiation and backpropagation in neurons of the mammalian CNS

Most neurons in the mammalian CNS encode and transmit information via action potentials. Knowledge of where these electrical events are initiated and how they propagate within neurons is therefore fundamental to an understanding of neuronal function. While work from the 1950s suggested that action potentials are initiated in the axon, many subsequent investigations have suggested that action potentials can also be initiated in the dendrites. Recently, experiments using simultaneous patch-pipette recordings from different locations on the same neuron have been used to address this issue directly. These studies show that the site of action potential initiation is in the axon, even when synaptic activation is powerful enough to elicit dendritic electrogenesis. Furthermore, these and other studies also show that following initiation, action potentials actively backpropagate into the dendrites of many neuronal types, providing a retrograde signal of neuronal output to the dendritic tree.

Dendritic spikes as a mechanism for cooperative long-term potentiation

Strengthening of synaptic connections following coincident pre- and postsynaptic activity was proposed by Hebb as a cellular mechanism for learning. Contemporary models assume that multiple synapses must act cooperatively to induce the postsynaptic activity required for hebbian synaptic plasticity. One mechanism for the implementation of this cooperation is action potential firing, which begins in the axon, but which can influence synaptic potentiation following active backpropagation into dendrites. Backpropagation is limited, however, and action potentials often fail to invade the most distal dendrites. Here we show that long-term potentiation of synapses on the distal dendrites of hippocampal CA1 pyramidal neurons does require cooperative synaptic inputs, but does not require axonal action potential firing and backpropagation. Rather, locally generated and spatially restricted regenerative potentials (dendritic spikes) contribute to the postsynaptic depolarization and calcium entry necessary to trigger potentiation of distal synapses. We find that this mechanism can also function at proximal synapses, suggesting that dendritic spikes participate generally in a form of synaptic potentiation that does not require postsynaptic action potential firing in the axon.

Dendritic glutamate receptor channels in rat hippocampal CA3 and CA1 pyramidal neurons

1. Properties of dendritic glutamate receptor (GluR) channels were investigated using fast application of glutamate to outside‐out membrane patches isolated from the apical dendrites of CA3 and CA1 pyramidal neurons in rat hippocampal slices. CA3 patches were formed (15‐76 microns from the soma) in the region of mossy fibre (MF) synapses, and CA1 patches (25‐174 microns from the soma) in the region of Schaffer collateral (SC) innervation. 2. Dual‐component responses consisting of a rapidly rising and decaying component followed by a second, substantially slower, component were elicited by 1 ms pulses of 1 mM glutamate in the presence of 10 microM glycine and absence of external Mg2+. The fast component was selectively blocked by 2‐5 microM 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX) and the slow component by 30 microM D‐2‐amino‐5‐phosphonopentanoic acid (D‐AP5), suggesting that the fast and slow components were mediated by the GluR channels of the L‐alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) and NMDA type, respectively. The peak amplitude ratio of the NMDA to AMPA receptor‐mediated components varied between 0.03 and 0.62 in patches from both CA3 and CA1 dendrites. Patches lacking either component were rarely observed. 3. The peak current‐voltage (I‐V) relationship of the fast component was almost linear, whereas the I‐V relationship of the slow component showed a region of negative slope in the presence of 1 mM external Mg2+. The reversal potential for both components was close to 0 mV. 4. Kainate‐preferring GluR channels did not contribute appreciably to the response to glutamate. The responses to 100 ms pulses of 1 mM glutamate were mimicked by application of 1 mM AMPA, whereas 1 mM kainate produced much smaller, weakly desensitizing currents. This suggests that the fast component is primarily mediated by the action of glutamate on AMPA‐preferring receptors. 5. The mean elementary conductance of AMPA receptor channels was about 10 pS, as estimated by non‐stationary fluctuation analysis. The permeability of these channels to Ca2+ was low (approximately 5% of the permeability to Cs+). 6. The elementary conductance of NMDA receptor channels was larger, with a main conductance state of about 45 pS. These channels were 3.6 times more permeable to Ca2+ than to Cs+.(ABSTRACT TRUNCATED AT 400 WORDS)

Dendritic Sodium Spikes Are Variable Triggers of Axonal Action Potentials in Hippocampal CA1 Pyramidal Neurons

Several early studies suggested that spikes can be generated in the dendrites of CA1 pyramidal neurons, but their functional significance and the conditions under which they occur remain poorly understood. Here, we provide direct evidence from simultaneous dendritic and somatic patch-pipette recordings that excitatory synaptic inputs can elicit dendritic sodium spikes prior to axonal action potential initiation in hippocampal CA1 pyramidal neurons. Both the probability and amplitude of dendritic spikes depended on the previous synaptic and firing history of the cell. Moreover, some dendritic spikes occurred in the absence of somatic action potentials, indicating that their propagation to the soma and axon is unreliable. We show that dendritic spikes contribute a variable depolarization that summates with the synaptic potential and can act as a trigger for action potential initiation in the axon.

Dendritic Calcium Spike Initiation and Repolarization Are Controlled by Distinct Potassium Channel Subtypes in CA1 Pyramidal Neurons

In CA1 pyramidal neurons of the hippocampus, calcium-dependent spikes occur in vivo during specific behavioral states and may be enhanced during epileptiform activity. However, the mechanisms that control calcium spike initiation and repolarization are poorly understood. Using dendritic and somatic patch-pipette recordings, we show that calcium spikes are initiated in the apical dendrites of CA1 pyramidal neurons and drive bursts of sodium-dependent action potentials at the soma. Initiation of calcium spikes at the soma was suppressed in part by potassium channels activated by sodium-dependent action potentials. Low-threshold, putative D-type potassium channels [blocked by 100 μm 4-aminopyridine (4-AP) and 0.5–1 μm α-dendrotoxin (α-DTX)] played a prominent role in setting a high threshold for somatic calcium spikes, thus restricting initiation to the dendrites. DTX- and 4-AP-sensitive channels were activated during sodium-dependent action potentials and mediated a large component of their afterhyperpolarization. Once initiated, repetitive firing of calcium spikes was limited by activation of putative BK-type calcium-activated potassium channels (blocked by 250 μm tetraethylammonium chloride, 70 nm charybdotoxin, or 100 nmiberiotoxin). Thus, the concerted action of calcium- and voltage-activated potassium channels serves to focus spatially and temporally the membrane depolarization and calcium influx generated by calcium spikes during strong, synchronous network excitation.

Postsynaptic depolarization requirements for LTP and LTD: a critique of spike timing-dependent plasticity.

Long-term potentiation and long-term depression require postsynaptic depolarization, which many current models attribute to backpropagating action potentials. New experimental work suggests, however, that other mechanisms can lead to dendritic depolarization, and that backpropagating action potentials may be neither necessary nor sufficient for synaptic plasticity in vivo.

Gamma-frequency oscillations: a neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity

Neurons are extraordinarily complicated devices, in which physical and chemical processes are intercoupled, in spatially non-uniform manner, over distances of millimeters or more, and over time scales of < 1 msec up to the lifetime of the animal. The fact that neuronal populations generating most brain activities of interest are very large-perhaps many millions of cells-makes the task of analysis seem hopeless. Yet, during at least some population activities, neuronal networks oscillate synchronously. The emergence of such oscillations generates precise temporal relationship between neuronal inputs and outputs, thus rendering tractable the analysis of network function at a cellular level. We illustrate this idea with a review of recent data and a network model of synchronized gamma frequency (> 20 Hz) oscillations in vitro, and discuss how these and other oscillations may relate to recent data on back-propagating, action potentials, dendritic Ca2+ transients, long-term potentiation and GABAA receptor-mediated synaptic potentials.

Cracking the neuronal code

How does the brain code information? Ferster and Spruston weigh the evidence in favor of a rate code (that the rate of action-potential firing carries the key information) and a temporal code (in which the pattern of firing is crucial, not just the rate).

Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites.

We performed simultaneous patch‐electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady‐state somatic voltage changes occurred at a distance of 238 μm from the soma in control and 409 μm after blocking the hyperpolarization‐activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100‐fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both.