Invited Symposium: Neuronal Histamine Systems and Behavior


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Regulation of Histamine Cell Firing

Contact Person: Helmut L Haas (haas@uni-duesseldorf.de)


Neuronal histamine is released diffusely in the whole brain from varicosities of axons whose cell bodies are located in the tuberomammillary nucleus of the hypothalamus (TM). One precondition to understand the functional implications of the histaminergic system in different behavioural situations is a knowledge of how neuronal activity in the histamine neurons arises. The firing activity of TM neurons is intrinsically controlled by an ensemble of membrane currents which maintain a stable firing rate in the absence of extrinsic control. Experiments in slices using microelectrodes indicate that TM neurons in vitro fire spontaneous actions potentials, at a stable rate in the range of 2 to 5 Hz, similar to the firing observed in vivo (2,4,6). Characteristic properties of these cells are the deep and broad afterhyperpolarizations following action potentials and the presence of prominent inward and outward rectification. In addition, we have observed failures of firing in which subthreshold depolarizations occur. In depolarized cells, such missed firings become more frequent, quite likely due to the inactivation of Na channels.

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Sodium Channels

In addition to the fast, inactivating sodium current responsible for sodium-dependent action potentials a slowly activating TTX-sensitive Na channel can be observed, which may contribute a depolarizing tone ensuring that the membrane potential eventually returns to threshold following the deep afterhyperpolarizations (AHPs). A two-compartment computational model of TM neurons shows that the activation kinetics of this channel are an important determinant of the shape of the AHP. It is a combination of the persistent sodium current and the subthreshold depolarization which eventually activate action potentials in TM neurons (4,7).

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Calcium Channels

Since subthreshold potentials persist in the presence of tetrodotoxin (which blocks voltage dependent Na channels in TM neurons) and are sensitive to Cd and Ni, these potentials appear to be mediated by calcium channels. TM neurons exhibit multiple, functionally different types of calcium channels. There is a transient, low threshold (T-type) channel which rapidly inactivates in a voltage-dependent manner. In addition, there is a high threshold calcium current sensitive to dihydropyridines which does not appreciably inactivate, similar to the L-type current. Finally, there is a calcium current which inactivates, exhibits an intermediate threshold for activation and which exhibits a voltage-dependent removal of inactivation. The current corresponds most closely to the N type. The intermediate threshold and the magnitude of the N type current make it a reasonable candidate for the subthreshold depolarization. The L-type current and the N type current likely combine to produce the calcium dependent action potentials which occur in TM neurons following treatment with TTX (6).

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Potassium Channels

TM neurons exhibit multiple potassium currents. Depolarization from the resting membrane potential activates a delayed rectifier which exhibits a relatively high threshold and very little inactivation. This current is blocked by 20 mM TEA, which in current clamp results in action potential broadening and the appearance of plateau potentials (2,6).

When the TM neuron is depolarized from a more negative membrane potential, a large outward current can be activated which inactivates as the sum of two exponentials. This transient outward current is in reality the sum of two transient potassium currents, with decay time constants in the range of 104 ms and 570 ms when recorded at 30 deg. C. When fully activated these currents are in the nanoampere range. If a fraction of this current is activated by an action potential, the result will be a hyperpolarizing current which will delay the return to threshold (2,3,6).

Functionally these currents are simlar to A currents, although the inactivation is much slower than most A currents. The faster of these currents is also sensitive to 4-AP, a blocker of IA. The decay time constants are more similar to those reported for the D current, a slowly inactivating transient outward current present in many central neurons, however the blocker of D current, dendrotoxin, failed to block either transient outward current in TM neurons. Both transient currents exhibit voltage dependent inactivation, must be hyperpolarized in order to fully remove inactivation, and under normal conditions will never be fully activated. Since both currents are large, this does not preclude a functional role in the activity of TM neurons.

TM neurons exhibit an apamin sensitive current. Apamin is best known as a blocker of the calcium dependent potassium channels responsible for slow afterhyperpolarizations in hippocampal as well as in other neurons (4). While the afterhyperpolarization of TM neurons is pronounced, it is relatively insensitive to blockers of calcium entry such as Cd, but is sensitive to apamin (2,4). Thus, the AHP may not be entirely due to activation of the apamin sensitve Ca dependent K channels, and may also depend on the delayed rectifier and/or the transient outward currents. Apamin treatment in TM neurons causes a depolarization as well as spike broadening, suggesting that the calcium activated current is partially activated at rest. This may indicate that there is a sustained calcium current in these neurons, possibly related to the intermediate-threshold calcium current previously mentioned.

Hyperpolarization of the membrane potential of TM neurons results in a decrease in the input resistance and a slow depolarization. This depolarization results from activation of a hyperpolarization-activated current referred to as IH. This current is the result of opening of voltage-dependent channels which are permeable to cations. Hyperpolarization of the membrane potential activates this current, resulting in an inward current which returns the membane to the resting level. IH has a reversal potential near -35 mV and activates negative to -55 mV. Thus, IH depolarizes over its entire activation range. The greater the hyperpolarization the faster and greater is the activation (3,6). IH can thus prevent sustained hyperpolarization of the cell. Due to its relatively hyperpolarized activation range, IH does not apear to affect firing activity under resting conditions in TM cells, but it has been shown in a number of cells to be modulated by cAMP, and under some conditions its activation range may be shifted, allowing it to influence firing activity. This has not so far been demonstrated in the TM.

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As can be appreciated from the above discussion, a number of membrane currents can influence the activty of TM neurons. Interaction of these currents results in the normal activity of TM neurons. The presence of multiple currents which exhibit inactivation, and which activate near threshold, leads to a dynamic equilibrium with the amount of activation dependent on previous activity of the neuron. The balance between hyperpolarizing and depolarizing influences assures the perturbations of the rhythm are corrected, with the resulting firing rate remaining quite stable.

A two-compartment (soma, dendrite) computational model was able to reproduce quite well the spontaneous firing of histaminergic TM neurons. Action potentials in TM neurons are mediated as usual by fast, inactivating sodium channels. High-threshold calcium channels are also activated by this depolarization and are responsible for the shoulder on the falling phase of the action potential as well as for the calcium influx which activates calcium-dependent potassium channels. Repolarization of the action potential and the initial phase of the deep afterhyperpolarization are primarily mediated by the delayed rectifier and the transient outward current. During the recovery from the AHP and the interspike interval, a number of different currents are active: the transient outward current, persistent sodium current, calcium-dependent potassium conductance and persistent calcium conductance (not yet incorporated into the model). The interplay between these different currents, which can be modulated by various neuroactive substances, determines finally the firing frequency of TM cells (5).


1. Greene RW, Haas HL and Reiner PB (1990) Two transient outward currents in histamine neurones of the rat hypothalamus in vitro. J. Physiol. Lond. 420:149-163.

2. Haas HL and Reiner PB (1988) Membrane properties of histaminergic tuberomammillary neurones of the rat hypothalamus in vitro. J. Physiol-Lond. 399:633-646.

3. Kamondi A and Reiner PB (1991) Hyperpolarization-activated inward current in histaminergic tuberomammillary neurons of the rat hypothalamus. J. Neurophysiol. 66:1902-11.

4. Llinas RR and Alonso A (1992) Electrophysiology of the mammillary complex in vitro. I. Tuberomammillary and lateral mammillary neurons. J. Neurophysiol. 68:1307-1320.

5. Schönrock B, Büsselberg D and Haas HL (1991) Properties of tuberomammillary histamine neurones and their response to galanin. Agents Actions 33:135-137.

6. Stevens DR and Haas HL (1996) Calcium-dependent prepotentials contribute to spontaneous activity in rat tuberomammillary neurons. J. Physiol.-Lond 493:747-754.

7. Uteshev V, Stevens DR and Haas HL (1995) A persistent sodium current in acutely isolated histaminergic neurons from rat hypothalamus. Neuroscience 66:143-149.

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Haas, H.L.; Stevens, D.R.; (1998). Regulation of Histamine Cell Firing. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/huston/haas0187/index.html
© 1998 Author(s) Hold Copyright