Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus

Biol Psychiatry. 2015 Mar 15;77(6):513-25. doi: 10.1016/j.biopsych.2014.03.013. Epub 2014 Mar 20.


Background: Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable.

Methods: Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures.

Results: Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks.

Conclusions: Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders.

Keywords: Antipsychotics; D(2) dopamine receptors; LTD; Memory; Neuronal plasticity; Temporal hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine D2 Receptor Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Learning / drug effects
  • Learning / physiology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / physiology*
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • RNA, Messenger / metabolism
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Space Perception / drug effects
  • Space Perception / physiology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology


  • DRD2 protein, mouse
  • Dopamine D2 Receptor Antagonists
  • RNA, Messenger
  • Receptors, Dopamine D2