Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning.

Hardy Hagena,Denise Manahan-Vaughan

doi:10.3389/fnsyn.2016.00031

Abstract

Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an important role for DA acting on D1/D5 receptors in the support of long-lasting and learning-related forms of synaptic plasticity at MF-CA3 synapses and provide further evidence for an important neuromodulatory role for this receptor in experience-dependent synaptic encoding in the hippocampal subfields.

Highlights

Synaptic plasticity in the hippocampus, in the form of longterm potentiation (LTP) and long-term depression (LTD), comprises the mechanistic foundation for learning and memory processes
Very long lasting forms of LTP and LTD are believed to comprise cellular correlates for long-term and persistent memory (Lynch, 2004; Malenka and Bear, 2004; Kemp and Manahan-Vaughan, 2007), and several studies report that the dopaminergic system, and in particular the D1/D5 receptors are important for the longevity of synaptic plasticity (Frey et al, 1990, 1991, 1993; Kulla and Manahan-Vaughan, 2000; Lemon and Manahan-Vaughan, 2006; Wiescholleck and Manahan-Vaughan, 2014)
D1/D5 antagonism impaired learning-facilitated plasticity. These results suggest that D1/D5 receptors are crucially involved in modulating synaptic plasticity at mossy fiber (MF)-CA3 synapses, and in modulating forms that are candidate processes for long-term memory

Summary

Introduction

Synaptic plasticity in the hippocampus, in the form of longterm potentiation (LTP) and long-term depression (LTD), comprises the mechanistic foundation for learning and memory processes. As experience-dependent phenomena, both LTP and LTD are strongly influenced by behavioral state and the neuromodulators that mediate state-dependency In this regard, the neurotransmitter dopamine (DA) stands out as a neuromodulator that is crucial for the fine-tuning of multiple hippocampal functions such as memory acquisition (O’Carroll et al, 2006; Bethus et al, 2010; Heath et al, 2015) and consolidation (Sara et al, 1999; Atherton et al, 2015), as well as in learning related to fear-conditioning (Inoue et al, 2000; Wen et al, 2014; Menezes et al, 2015). D1/D5-receptors are highly expressed in area CA3 of the hippocampus (Ariano et al, 1997; Ciliax et al, 2000; Khan et al, 2000), whereas D2-like receptor expression in area CA3 seems to be relatively sparse (Goldsmith and Joyce, 1994; Gangarossa et al, 2012)

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