Info

NMDAR-dependent LTD

mGluR-dependent LTD

Endocannabinoid/Endovanilloid-mediated LTD

Synapses expressing

SC-CA! pyramidal neuron

SC-CA1 pyramidal neuron, SC-CA1 s. radiatum interneuron

SC-CA1 pyramidal neuron, SC-CA1 s.radiatum interneuron

Induction protocol

Low-frequency stimulation (LFS), 0.5-3.0 Hz, typically 1 Hz for 15 mins

Paired-pulse low-frequency stimulation (PP-LFS), typically 1 Hz for 15 min; Application of DHPG

PP-LFS, typically 1 Hz for 15 mins; application of DHPG; high-frequency stimulation (HFS); e.g., 100 Hz (x 2, 20 s inter-train interval)

Mechanism of induction

Postsynaptic: NMDAR activation; Ca2+ influx and release from intracellular stores

Postsynaptic: Group 1 mGluR activation; Ca2+ influx

Postsynaptic: Group 1 mGluR activation; Ca2+ influx; phosphoinositide hydrolysis; release of retrograde messengers

Mechanism of expression

Postsynaptic: Activation of protein phosphatase, calcineurin, PP!; PSD-95 degradation; modification and internalization of AMPARs; protein synthesis

Postsynaptic: Activation of protein tyrosine phosphatase, p38 mitogen activated protein kinase cascade, PI3K and Ras-activated ERK; AMPAR internalization; protein synthesis

Presynaptic: Activation of presynaptic receptors e.g., CB1 and TRPV1 by retrograde messengers; decreased presynaptic neurotransmitter release

AMPAR a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate acid glutamate receptor;CB/ cannabinoid type 1 receptor;DHPG Dihydroxyphenyl-glycine;HFS high-frequency stimulation;hertz (Hz); mGluR metabotropic glutamate receptor;NMDAR N-methyl-D-aspartate glutamate receptor; PI3K phosphoinositide-3 kinase;PP! protein phosphatase;PP-LFS paired-pulse low-frequency stimulation PSD-95 postsynaptic density-95;TRPV! transient receptor potential vanilloid 1;SC Schaffer collateral

AMPAR a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate acid glutamate receptor;CB/ cannabinoid type 1 receptor;DHPG Dihydroxyphenyl-glycine;HFS high-frequency stimulation;hertz (Hz); mGluR metabotropic glutamate receptor;NMDAR N-methyl-D-aspartate glutamate receptor; PI3K phosphoinositide-3 kinase;PP! protein phosphatase;PP-LFS paired-pulse low-frequency stimulation PSD-95 postsynaptic density-95;TRPV! transient receptor potential vanilloid 1;SC Schaffer collateral

Long-Term Depression and Memory. Fig. 1. Original experimental data of Dudek and Bear (1992) showing NMDA receptor-dependent LTD in the hippocampus. In the presence of the NMDA receptor antagonist AP5, low-frequency synaptic stimulation (1 Hz for 15 min) produces no change in the synaptic response. When AP5 is washed off, the same low-frequency synaptic stimulation now produces a decrease in synaptic responses: LTD. (Reproduced from Dudek S, Bear M (1992) Homosynaptic long-term depression in area CA1 of hippocampus and effects of N-methyl-D-aspartate receptor blockade. Proc Natl Acad Sci USA 89: 4363-4367 with permission.)

recognition of a novel environment in rats correlates well with the facilitation of homosynaptic NMDAR-dependent CA1 LTD. Hippocampal LTD is also enhanced by stress, which may be significant in stress-induced cognitive impairment. Overall, evidence suggests that LTD in the hippocampus is associated with at least certain forms of learning and memory (Massey and Bashir 2007).

LTD in the Ventral Tegmental Area (VTA)

The VTA is a midbrain nucleus containing dopaminergic neurons that project to the ventral striatum and the prefrontal cortex, along with nondopaminergic projection and local circuit neurons, some of which are GABAergic. Ascending mesocorticolimbic dopaminergic pathways along with nigrostriatal pathways play a role in internally generated movements, motivation and reward processing, learning, and cognitive functions, including nondeclara-tive forms of learning and memory. From a psychophar-macological perspective, these pathways are interesting because they are targets for drugs of abuse and are likely target sites for ► anti-psychotic drugs.

A substantial body of literature suggests that gluta-matergic synaptic plasticity in dopaminergic pathways may contribute to reward-related learning and the neuronal plasticity mechanisms underlying drug ► addiction (reviewed by Kauer and Malenka 2007; Wolf et al. 2004). Persistent forms of synaptic plasticity have been described in dopaminergic pathways (reviewed by Kauer 2004; Kauer and Malenka 2007; Wolf et al. 2004). A form of LTD at glutamatergic synapses was first described in VTA dopaminergic neurons in 2000. This form of VTA LTD was not dependent on either NMDARs or mGluRs, but did require an increase in intracellular Ca2+, most likely via influx through voltage-gated Ca2+ channels, subsequent activation of a novel signaling mechanism utilizing protein kinase A, and downregulation of AMPARs. A second form of mGluR-dependent LTD is also expressed in VTA (Bellone and Lüscher 2006).

VTA LTD has been proposed as a potential "brake" on dopaminergic neuron excitability (Kauer 2004), as weakening excitatory synaptic strength would limit the tonic and phasic excitatory drive to these neurons from cortical and brainstem regions, potentially minimizing opportunities for synaptic strengthening such as ► long-term potentiation. Removal of this "braking" mechanism is a plausible route for psychoactive drugs to manipulate synaptic plasticity in dopaminergic pathways and drive forms of learning that may be dysfunctional, such as habit learning in drug addiction.

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