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
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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