Molecular and functional remodeling of electrogenic membrane of hypothalamic neurons in response to changes in their input

Abstract

Neurons respond to stimuli by integrating generator and synaptic potentials and generating action potentials. However, whether the underlying electrogenic machinery within neurons itself changes, in response to alterations in input, is not known. To determine whether there are changes in Na ؉ channel expression and function within neurons in response to altered input, we exposed magnocellular neurosecretory cells (MNCs) in the rat supraoptic nucleus to different osmotic milieus by salt-loading and studied Na ؉ channel mRNA and protein, and Na ؉ currents, in these cells. In situ hybridization demonstrated significantly increased mRNA levels for ␣-II, Na6, ␤1 and ␤2 Na ؉ channel subunits, and immunohistochemistr y͞immunoblotting showed increased Na ؉ channel protein after salt-loading. Using patch-clamp recordings to examine the deployment of functional Na ؉ channels in the membranes of MNCs, we observed an increase in the amplitude of the transient Na ؉ current after salt-loading and an even greater increase in amplitude and density of the persistent Na ؉ current evoked at subthreshold potentials by slow ramp depolarizations. These results demonstrate that MNCs respond to salt-loading by selectively synthesizing additional, functional Na ؉ channel subtypes whose deployment in the membrane changes its electrogenic properties. Thus, neurons may respond to changes in their input not only by producing different patterns of electrical activity, but also by remodeling the electrogenic machinery that underlies this activity.The nervous system responds to environmental stimuli with altered patterns of electrical activity that trigger physiological responses and behaviors that tend to protect the organism and͞or help it adapt to its environment. The molecular and cellular mechanisms underlying these altered patterns of neuronal activity are not fully understood. They depend, in part, on the integration of generator potentials and excitatory and inhibitory postsynaptic potentials that impinge on neurons within the circuit under study. Whether the electrogenic machinery responsible for this signal integration within these neurons itself changes, however, in response to environmental changes is not well understood.A model for studying the neuronal response to environmental changes is provided by the magnocellular neurosecretory cells (MNCs) in the supraoptic nucleus (SON), which send axons to the neurohypophysis and fire in bursts so as to release vasopressin in response to increases in plasma osmolality. Vasopressin release is a function of action potential frequency in these cells (1, 2) and firing frequency, in turn, is modulated by osmotic stimuli (3-5). Action potential activity in these cells is Na ϩ dependent and tetrodotoxin (TTX) sensitive, indicating that it is mediated by Na ϩ channels (6-9). While it is known that eight types of Na ϩ channels, encoded by distinct genes, are expressed in neurons (10-17), the identity of the Na ϩ channels in supraoptic MNCs is not known. Moreover, the basic mechanisms that ...

Somato-dendritic mechanisms underlying the electrophysiological properties of hypothalamic magnocellular neuroendocrine cells: A multicompartmental model study

“…The function for the time constant of inactivation of the potassium current (τ n ) was selected as the sum of three Boltzmann functions in order to provide correspondence of spike shape and duration. The structure of the model provides a good fit to published results from voltage-clamp experiments Tanaka et al 1999) and produces spikes with amplitude and duration similar to those observed in MNCs. Steady-state activation and inactivation characteristics of I Na , I K(DR) and I A are presented in Fig.…”

“…1, the model contains several voltage-gated currents: the transient voltage-gated sodium current (I Na ) (Tanaka et al 1999), the delayed rectifier potassium current (I K(DR) ) , the A-type transient potassium current (I A ) , and L-and Ntype Ca 2+ currents (I Ca,L , I Ca,N ) (Foehring and Armstrong 1996;Joux et al 2001). It also contains the following Ca 2+ -dependent currents: a K + current mediated by large conductance K + (BK) channels (Dopico et al 1999), a K + current mediated by small conductance K + (SK) channels (Kirkpatrick and Bourque 1996), a non-selective cation (CAN) current (I CAN ) (Ghamari-Langroudi and Bourque 2002), and a slowly activated K + current in OT neurons Armstrong 1995,1997).…”

“…For model simplicity, we used the steady state value of activation for the sodium current (m ∞ ), because we focused on the electrophysiological processes, which are much longer than single spike rising phase. The function for the time constant of inactivation (τ h ) of this current was selected as the sum of two Boltzmann functions in order to satisfy the dynamics of the sodium current in voltage clamp experiments in freshly isolated SON neurons (Tanaka et al 1999). The function for the time constant of inactivation of the potassium current (τ n ) was selected as the sum of three Boltzmann functions in order to provide correspondence of spike shape and duration.…”

“…The activation and inactivation properties of voltage-gated currents were extracted from available voltage-clamp data from MNCs (Joux et al 2001;Tanaka et al 1999), and from other types of mammalian CNS neurons (Hoffman et al 1997;Migliore and Shepherd 2002). The main criteria for determining the distribution of channels were simulations of appropriate physiological responses for MNCs for different experimental protocols.…”

The molecular basis for electrogenic computation in the brain: you can't step in the same river twice

“…[27][28][29] My colleagues and I recently tested the hypothesis that the transition from the quiescent to the bursting state includes a rebuilding of these cells' electrogenic membrane via the expression of a new repertoire of sodium channels. 30 To test this hypothesis, we studied magnocellular neurons under normal conditions and following salt-loading, which exposes supraoptic neurons to a milieu of elevated extracellular osmolality and triggers a transition to a bursting state.…”