Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells

Abstract

The mechanisms underlying memory formation in the hippocampal network remain a major unanswered aspect of neuroscience. Although high-frequency activity appears essential for plasticity, salience for memory formation is also provided by activity in ventral tegmental area (VTA) dopamine projections. Here, we report that activation of dopamine D1 receptors in dentate granule cells (DGCs) can preferentially increase dendritic excitability to both highfrequency afferent activity and high-frequency trains of backpropagating action potentials. Using whole-cell patch clamp recordings, calcium imaging, and neuropeptide Y to inhibit postsynaptic calcium influx, we found that activation of dendritic voltagedependent calcium channels (VDCCs) is essential for dopamineinduced long-term potentiation (LTP), both in rat and human dentate gyrus (DG). Moreover, we demonstrate previously unreported spike-timing-dependent plasticity in the human hippocampus. These results suggest that when dopamine is released in the dentate gyrus with concurrent high-frequency activity there is an increased probability that synapses will be strengthened and reward-associated spatial memories will be formed.A s an animal explores a specific location, place cells in the dentate gyrus (DG) of the hippocampus fire bursts of action potentials (APs) (1) that can result in the formation of a new, long-term contextual memory (2). This is part of the "pattern separation" mechanism, whereby only a small population of dentate granule cells (DGCs) become very active and pass on the incoming cortical input to be later represented or "completed," in the downstream CA3 network (3). Memory formation related to a specific place can be enhanced by an associated salience, such as reward (4). Recent work suggests that disruption of mesocorticolimbic dopamine responses blocks conditioned place preference (CPP), a reward-driven form of spatial memory (5, 6). Furthermore, nicotine-induced CPP requires dopamine D1 receptor (D1R) activation in the DG (7). The medial perforant pathway (MPP) carries spatial information to the middle third of the molecular layer (8). In DGCs, D1Rs are concentrated throughout the dendritic tree (9). This suggests that bursting activity in DGCs, coincident with local dopamine release, may enhance formation of salient memories, but a mechanism remains unknown.One potential mechanism mediating plasticity is the coincidence of backpropagating dendritic APs with appropriately timed synaptic input (10); this mechanism requires postsynaptic Ca 2+ influx (11). Ca 2+ channels have been implicated in nonlinear, frequency-dependent responses in dendrites (12) and D1Rs can potentiate dendritic excitability in hippocampal area CA1 (13). Because the molecular layer of the DG is innervated by dopaminergic terminals from the ventral tegmental area (VTA) (14) we examined the possibility that interactions at the level of DGC dendrites between firing frequency, dendritic Ca 2+ responses, and D1Rs, may mediate plasticity in medial perforant path synaptic inputs....

Hippocampal receptor complexes paralleling LTP reinforcement in the spatial memory holeboard test in the rat

“…An in vivo study has shown that the D1R is crucial for maintenance of LTP in CA1 but does not modulate LTP in the dentate gyrus [83] when measured over 4 hours without a specific behavioural context. However, modulatory inputs affecting the dopaminergic system and enhancing LTP in the dentate gyrus have been reported in a context of reward [54,1,42] and reward associated spatial memories [53,37]. These and the present study suggest that previous activity and incoming information during LTP-induction significantly determines different mechanisms involved in LTP-maintenance.…”

D1 and D5 dopamine receptors participate on the consolidation of two different memories

“…For example, the activation of D1-family receptors alters excitability in the hippocampus [64,65] and therefore influences the thresholds for the induction of synaptic plasticity or memory encoding. Different hippocampal subregions such as the dentate gyrus, CA1 and subiculum that exert distinct functions in information processing are also modulated by the activation of D1 receptors [37,[66][67][68][69].…”

Chronic Fluoxetine Selectively Upregulates Dopamine D1-Like Receptors in the Hippocampus

“…These enhanced monoaminergic modulations would greatly increase excitatory drive to CA3 pyramidal cells by the mossy fibers. Furthermore, increased D 1 -like receptor expression in the granule cells may facilitate the induction of long-term potentiation at the perforant path granule cell synapse (Hamilton et al, 2010;Kusuki et al, 1997). Together with changes in intrinsic functional properties of granule cells caused by dematuration, the altered monoaminergic synaptic modulation is likely to have a significant impact on propagation of neuronal signals through the dentate gyrus, thereby possibly contributing to neuronal bases for mechanisms of action of SSRIs.…”