The Journal of Neurophysiology Vol. 77 No. 4 April 1997, pp. 1829-1843
Copyright ©1997 The American Physiological Society

Ionic Mechanisms of Muscarinic Depolarization in Entorhinal Cortex Layer II Neurons

Ruby Klink and Angel Alonso

Department of Neurology and Neurosurgery, Montreal Neurological Institute and McGill University, Montreal, Quebec H3A 2B4, Canada

Klink, Ruby and Angel Alonso. Ionic mechanisms of muscarinic depolarization in entorhinal cortex layer II neurons. J. Neurophysiol. 77: 1829-1843, 1997. The mechanisms underlying direct muscarinic depolarizing responses in the stellate cells (SCs) and non-SCs of medial entorhinal cortex layer II were investigated in tissue slices by intracellular recording and pressure-pulse applications of carbachol (CCh). Subthreshold CCh depolarizations were largely potentiated in amplitude and duration when paired with a short DC depolarization that triggered cell firing. During Na⁺ conductance block, CCh depolarizations were also potentiated by a brief DC depolarization that allowed Ca²⁺ influx and the potentiation was more robust in non-SCs than in SCs. Also, in non-SCs, CCh depolarizations could be accompanied by spikelike voltage oscillations at a slow frequency. In both SCs and non-SCs, the voltage-current (V-I) relations were similarly affected by CCh, which caused a shift to the left of the steady-state V-I relations over the entire voltage range and an increase in apparent slope input resistance at potentials positive to about 70 mV. CCh responses potentiated by Ca²⁺ influx demonstrated a selective increase in slope input resistance at potentials positive to about 75 mV in relation to the nonpotentiated responses. K⁺ conductance block with intracellular injection of Cs⁺ (3 M) and extracellular Ba²⁺ (1 mM) neither abolished CCh depolarizations nor resulted in any qualitatively distinct effect of CCh on the V-I relations. CCh depolarizations were also undiminished by block of the time-dependent inward rectifier I_h with extracellular Cs⁺. However, CCh depolarizations were abolished during Ca²⁺ conductance block with low-Ca²⁺ (0.5 mM) solutions containing Cd²⁺, Co²⁺, or Mn²⁺, as well asby intracellular Ca²⁺ chelation with bis-(o-aminophenoxy)-N,N,N,N-tetraacetic acid. Inhibition of the Na⁺-K⁺ ATPase with strophanthidin resulted in larger CCh depolarizations. On the other hand, when NaCl was replaced by N-methyl-D-glucamine, CCh depolarizations were largely diminished. CCh responses were blocked by 0.8 µM pirenzepine, whereas hexahydro-sila-difenidolhydrochloride,p-fluoroanalog (p-F-HHSiD) and himbacine were only effective antagonists at 5- to 10-fold larger concentrations. Our data are consistent with CCh depolarizations being mediated in both SCs and non-SCs by m1 receptor activation of a Ca²⁺-dependent cationic conductance largely permeable to Na⁺. Activation of this conductance is potentiated in a voltage-dependent manner by activity triggering Ca²⁺ influx. This property implements a Hebbian-like mechanism whereby muscarinic receptor activation may only be translated into substantial membrane depolarization if coupled to postsynaptic cell activity. Such a mechanism could be highly significant in light of the role of the entorhinal cortex in learning and memory as well as in pathologies such as temporal lobe epilepsy.

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