Abstract
Long-term potentiation (LTP) of Schaffer collateral (SC) synapses in the hippocampus is thought to play a key role in episodic memory formation. Because the hippocampus is a shorter-term, limited capacity storage system, repeated bouts of learning and synaptic plasticity require that SC synapses reset to baseline at some point following LTP. We previously showed that repeated low frequency activation of temperoammonic (TA) inputs to the CA1 region depotentiates SC LTP without persistently altering basal transmission. This heterosynaptic depotentiation involves adenosine A1 receptors but not N-methyl-D-aspartate receptors, metabotropic glutamate receptors or L-type calcium channels. In the present study, we used rat hippocampal slices to explore other messengers contributing to TA-induced SC depotentiation, and provide evidence for the involvement of cannabinoid-1 and γ-aminobutyric acid (GABA) type-A receptors as more proximal signaling events leading to synaptic resetting, with A1 receptor activation serving as a downstream event. Surprisingly, we found that TA-induced SC depotentiation is independent of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate glutamate receptors. We also examined the involvement of mitogen-activated protein kinases (MAPKs), and found a role for extracellular-signal related kinase 1/2 and p38 MAPK, but not c-Jun-N-terminal kinase. These results indicate that low frequency stimulation of TA inputs to CA1 activates a complex signaling network that instructs SC synaptic resetting. The involvement of GABA and endocannabinoids suggest mechanisms that could contribute to cognitive dysfunction associated with substance abuse and neuropsychiatric disorders.
Highlights
Defects in learning and memory accompany neuropsychiatric disorders and are a leading cause of illness-related disability
Because our prior studies found no role for N-methyl-D-aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs) [11], and glutamate is the principal neurotransmitter in the TA path from entorhinal cortex to stratum lacunosum moleculare (SLM) [14,15], we examined the effects of inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors
We found that the MEK inhibitor, PD98059 (10 μM), which prevents signaling in the ERK 1/2 pathway (159.5 ± 15.6% after high frequency stimulation (HFS) and 147.2 ± 15.7% after PLFS, n = 8, Fig 6A), and the p38 mitogen-activated protein kinases (MAPKs) inhibitor, SB20358 (10 μM) (160.5 ± 16.5% after HFS and 155.3 ± 12.2% after PLFS, n = 5, Fig 6B) [11], independently blocked the effects of TA stimulation on long-term potentiation (LTP), suggesting a role for these MAPKs in heterosynaptic depotentiation
Summary
Defects in learning and memory accompany neuropsychiatric disorders and are a leading cause of illness-related disability. LTP and LTD have been extensively studied in the hippocampus, a brain region that processes new declarative memories and is involved in psychiatric illnesses. Because the hippocampus is involved in initial memory formation, operates over a restricted range of synaptic efficacy, and has limited storage capacity, this is an important question for understanding the dysfunction of neuropsychiatric illnesses. There are at least three ways that synaptic resetting can occur These include homeostatic changes in which neurons adjust in response to longerlived changes in activity by cell autonomous mechanisms [3]. These include homosynaptic depotentiation (LTP-D), in which the same inputs that undergo LTP trigger resetting [4,5], or heterosynaptic depotentiation in which other inputs drive resetting [6]. Homosynaptic LTP-D involves serine phosphatases, but differs from LTD in the role of specific subtypes of mitogen-activated protein kinases (MAPKs) [8,9,10]
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