The Modulation of Synaptic Function by Dopamine in the Lateral Entorhinal Cortex

Abstract

Forming new declarative memories requires integrating sensory information in the entorhinal cortex and its transfer through the hippocampal circuit. To understand the entorhinal cortex's role in cognition, factors affecting superficial layer projection neuron excitability and mechanisms of sensory information encoding must be identified. Modulatory neurotransmitter systems shape synaptic processes required for encoding and retaining information and influence membrane excitability. The neurotransmitter dopamine, linked to Schizophrenia and Parkinson’s disease also regulates learning and memory. Dopaminergic neurons from the ventral tegmental area project widely, including to the lateral entorhinal cortex, strongly affecting neuron responsiveness and excitability. However, the effects of dopamine on synaptic plasticity remain unclear. To investigate this, intra- and extracellular electrophysiological recordings, pharmacological interventions, and neuronal tracing were used to assess synaptic transmission, plasticity, and cellular morphology in rat lateral entorhinal cortex slices in vitro. Results showed that dopamine suppressed sensory inputs to the lateral entorhinal cortex via a D2 receptor-mediated reduction in glutamate release from sensory afferents projecting to the superficial layers. Dopamine application paired with low-frequency stimulation blocked activity-dependent LTD, but this was reversed by a priming application of dopamine, which triggered clathrin-dependent internalisation of dopaminergic receptors for up to 3 hours. Previous exposure to dopamine affected future responsiveness to the agonist, potentially representing a novel form of metaplasticity in the lateral entorhinal cortex. Blocking metabotropic receptor desensitisation with the β-arrestin inhibitor, barbadin, prevented receptor internalisation and restored the dopamine-mediated block of LTD. Tetanic stimulation intended to induce LTP in sensory inputs to superficial layer II induced LTD instead, mediated partly by stimulation-induced changes in local inhibition and dopaminergic tone. Superficial layer projection neurons are resistant to LTP induction, but methods to boost NMDA receptor activation restored the capacity of these neurons to support short-term potentiation following high frequency stimulation. Together, these data highlight multiple mechanisms by which dopamine exposure can modulate sensory and mnemonic processing in the medial temporal lobe. This modulation occurs through the regulation of basal synaptic transmission and activity-dependent plasticity in the lateral entorhinal cortex.