ABSTRACT
The modulatory neurotransmitter dopamine induces concentration-dependent changes in synaptic transmission in the entorhinal cortex, in which high concentrations of dopamine suppress evoked excitatory postsynaptic potentials (EPSPs) and lower concentrations induce an acute synaptic facilitation. Whole-cell current-clamp recordings were used to investigate the dopaminergic facilitation of synaptic responses in layer II neurons of the rat lateral entorhinal cortex. A constant bath application of 1 µM dopamine resulted in a consistent facilitation of EPSPs evoked in layer II fan cells by layer I stimulation; the size of the facilitation was more variable in pyramidal neurons, and synaptic responses in a small group of multiform neurons were not modulated by dopamine. Isolated inhibitory synaptic responses were not affected by dopamine, and the facilitation of EPSPs was not associated with a change in paired-pulse facilitation ratio. Voltage-clamp recordings of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptor-mediated excitatory postsynaptic currents (EPSCs) were facilitated by dopamine, but N-methyl-D-aspartate receptor-mediated currents were not. Bath application of the dopamine D1-like receptor blocker SCH23390 (50 µM), but not the D2-like receptor blocker sulpiride (50 µM), prevented the facilitation, indicating that it is dependent upon D1-like receptor activation. Dopamine D1 receptors lead to activation of protein kinase A (PKA), and including the PKA inhibitor H-89 or KT 5720 in the recording pipette solution prevented the facilitation of EPSCs. PKA-dependent phosphorylation of inhibitor 1 or the dopamine- and cAMP-regulated protein phosphatase (DARPP-32) can lead to a facilitation of AMPA receptor responses by inhibiting the activity of protein phosphatase 1 (PP1) that reduces dephosphorylation of AMPA receptors, and we found here that inhibition of PP1 occluded the facilitatory effect of dopamine. The dopamine-induced facilitation of AMPA receptor-mediated synaptic responses in layer II neurons of the lateral entorhinal cortex is therefore likely mediated via a D1 receptor-dependent increase in PKA activity and a resulting inhibition in PP1-dependent dephosphorylation of AMPA receptors.
Subject(s)
Dopamine/metabolism , Entorhinal Cortex/physiology , Neurons/physiology , Receptors, Dopamine D1/metabolism , Synaptic Transmission/physiology , Animals , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Cyclic AMP-Dependent Protein Kinases/metabolism , Dopamine Antagonists/pharmacology , Dopamine D2 Receptor Antagonists , Dopamine and cAMP-Regulated Phosphoprotein 32/metabolism , Entorhinal Cortex/drug effects , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , In Vitro Techniques , Male , Neurons/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Phosphatase 1/metabolism , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Rats , Rats, Long-Evans , Receptors, AMPA/metabolism , Receptors, Dopamine D1/antagonists & inhibitors , Receptors, Dopamine D2/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Transmission/drug effectsABSTRACT
Layer II of the parasubiculum (PaS) receives excitatory synaptic input from the CA1 region of the hippocampus and sends a major output to layer II of the medial and lateral entorhinal cortex. The PaS also receives heavy cholinergic innervation from the medial septum, which contributes to the generation of theta-frequency (4-12 Hz) electroencephalographic (EEG) activity. Cholinergic receptor activation exerts a wide range of effects in other areas of the hippocampal formation, including membrane depolarization, changes in neuronal excitability, and suppression of excitatory synaptic responses. The present study was aimed at determining how cholinergic receptor activation modulates excitatory synaptic input to the layer II/III neurons of the PaS in acute brain slices. Field excitatory postsynaptic potentials (fEPSPs) in layer II/III of the PaS were evoked by stimulation of either layer I afferents, or ascending inputs from layer V. Bath-application of the cholinergic agonist carbachol (0.5-10 µM) suppressed the amplitude of fEPSPs evoked by both superficial- and deep layer stimulation, and also enhanced paired-pulse facilitation. Constant bath-application of the GABA(A) antagonist bicuculline (10 µM) failed to eliminate the suppression, indicating that the cholinergic suppression of fEPSPs is not due to increased inhibitory tone. The muscarinic receptor antagonist atropine (1 µM) blocked the suppression of fEPSPs, and the selective M(1)-preferring receptor antagonist pirenzepine (1 µM), but not the M(2)-preferring antagonist methoctramine (1-5 µM), also significantly attenuated the suppression. Therefore, cholinergic receptor activation suppresses excitatory synaptic input to layer II/III neurons of the PaS, and this suppression is mediated in part by M(1) receptor activation.