Abstract
The lateral entorhinal cortex receives strong inputs from midbrain dopamine neurons that can modulate its sensory and mnemonic function. We have previously demonstrated that 1 µM dopamine facilitates synaptic transmission in layer II entorhinal cortex cells via activation of D1-like receptors, increased cAMP-PKA activity, and a resulting enhancement of AMPA-receptor mediated currents. The present study assessed the contribution of phosphatidylinositol (PI)-linked D1 receptors to the dopaminergic facilitation of transmission in layer II of the rat entorhinal cortex, and the involvement of phospholipase C activity and release of calcium from internal stores. Whole-cell patch-clamp recordings of glutamate-mediated evoked excitatory postsynaptic currents were obtained from pyramidal and fan cells. Activation of D1-like receptors using SKF38393, SKF83959, or 1 µM dopamine induced a reversible facilitation of EPSCs which was abolished by loading cells with either the phospholipase C inhibitor U-73122 or the Ca2+ chelator BAPTA. Neither the L-type voltage-gated Ca2+ channel blocker nifedipine, nor the L/N-type channel blocker cilnidipine, blocked the facilitation of synaptic currents. However, the facilitation was blocked by blocking Ca2+ release from internal stores via inositol 1,4,5-trisphosphate (InsP3) receptors or ryanodine receptors. Follow-up studies demonstrated that inhibiting CaMKII activity with KN-93 failed to block the facilitation, but that application of the protein kinase C inhibitor PKC(19-36) completely blocked the dopamine-induced facilitation. Overall, in addition to our previous report indicating a role for the cAMP-PKA pathway in dopamine-induced facilitation of synaptic transmission, we demonstrate here that the dopaminergic facilitation of synaptic responses in layer II entorhinal neurons also relies on a signaling cascade dependent on PI-linked D1 receptors, PLC, release of Ca2+ from internal stores, and PKC activation which is likely dependent upon both DAG and enhanced intracellular Ca2+. These signaling pathways may collaborate to enhance sensory and mnemonic function in the entorhinal cortex during tonic release of dopamine.
Highlights
The entorhinal cortex is an essential parahippocampal region through which multimodal sensory information from the neocortex reaches the hippocampal formation [1], and it is thought to contribute significantly to the sensory and mnemonic functions of the medial temporal lobe [2]
Because we found that protein kinase A (PKA) signaling was required for the dopamine-mediated facilitation of excitatory postsynaptic currents (EPSCs) [20], and phosphatase 1 (PP1) regulates phosphorylation of L- and N-type voltagegated calcium channels (VGCCs) [36,37,38], our first experiments tested the involvement of L- and Ntype VGCCs in the dopaminergic facilitation of synaptic transmission
Consistent with our previous findings that 1 μM dopamine induces a reversible D1-like receptor-dependent facilitation of AMPA receptor-mediated EPSCs in entorhinal cells [20], we found here that 5 min bath application of the selective D1-receptor agonist SKF38393 (10 μM) facilitates EPSCs in lateral entorhinal cortex cells held at -60 mV (Fig 1A1)
Summary
The entorhinal cortex is an essential parahippocampal region through which multimodal sensory information from the neocortex reaches the hippocampal formation [1], and it is thought to contribute significantly to the sensory and mnemonic functions of the medial temporal lobe [2]. The cell islands of layer II of the lateral entorhinal cortex receive one of the largest cortical projections from midbrain dopamine neurons that contribute to appetitive motivation and learning [10,11,12,13,14,15]. The exact functions played by dopamine in the superficial layers of the lateral entorhinal cortex are presently poorly understood, effects of dopamine on synaptic transmission suggest that low concentrations of dopamine may act to enhance the salience of synaptic inputs received from sensory regions. Low to moderate levels of D1-like receptor activation enhance synaptic transmission and working memory function in the prefrontal cortex [21,22,23], and dopamine may act in the superficial layers of the lateral entorhinal cortex
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