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A Biophysical Model of Endocannabinoid-Mediated Short Term Depression in Hippocampal Inhibition

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Introducción

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  • Cannabinoid signalling is an important modulator of plasticity for both inhibitory and excitatory plasticity
  • eCB have a unconventional retrograde signalling system important for many physiological processes
  • eCBs produce eCB-iSTD (produced by reduction in the release of GABA from interneurons) and eCB-eSTD (produced by reduction in the release of GLU from excitatory neurons).
  • eCB synthesis is stimulated by depolarization and subsequent increases in intracellular Ca2+.
  • eCB can produce both DSE and DSI in hippocampus, but DSE are more prominent
  • Another effects of eCBs are MSI/MSE by activation of some Gq/11 linked receptors.
  • This form of plasticity is linked more closely to Group I metabotropic glutamate receptors and metabotropic muscarinic receptors (M1/M3).
  • MSI/MSE seem to be relatively independent of transients in intracellular Ca2+
  • eCB is also involved in long lasting forms of plasticity LTP/LTD
  • Currently (2013) all models of eCB dynamics are phenomenological and at a network level
  • This is the gap the paper address, describing a model at synapse level.

Neurobiology of Cannabinoid Signalling During DSI

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eCB Synthesis in the Post-synaptic Cell

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  • In this case 2-AG was considered in the model, rather than AEA given 2-AG is the main eCB in hippocampus and it is more prevalent as fast retrograde synaptic messenger
  • Synthesis machinery for 2-AG production is predominately found at the spines on the dendrites of hippocampal pyramidal cell facing glutamatergic terminals
  • But CB1 is expressed at very high levels in inhibitory terminals of CCK positive perisomatic basket cells.

PLC β-independent

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  • Produced by increases in intracellular Ca2+ concetration, produced by VGCCs.
  • Rises in intracellular Ca2+ during DSI are considered to be mainly a product of the activity of L-type VGCCs
  • Also RyR release from ER, and calcium entry by the NMDAR may contribute
  • This calcium at micro-molecular concentrations induce synthesis of DAG through a undetermined pathway that is independent of PLCβ

PLC β-dependent

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  • Produced by Gq/11-coupled receptors activation that stimulates PLCβ
  • PLCβ cleaves PIP2 into DAG and IP3
  • DAG is then converted to 2-AG by DGLα and released to the synaptic cleft

eCB transport and degradation

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  • It not well understood if 2-AG diffuses through the membranes of originating cells or if it is transported across them
  • 2-AG is returned into the cells by an unknown eCB transporter where most of it is degraded by MGL

Modelling Strategy

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Post neuron:

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  • Single compartment
  • Excitatory neuron
  • eCB synthesis mecanism mediated by calcium dynamics
  • L-type VGCCs activity <–Hill function–> 2-AG synthesis

Pre neuron

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  • Single compartment
  • CB receptor dynamics
  • Inhibitory neuron
  • Bertram et al. model for synaptic facilitation and depression of GABA release via N-type VGCCs

Variables

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  • Differential activation of CB1 by 2-AG / WIN55,212

Results

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eCB-iSTD Magnitude Depends on CB Agonist Concentration

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  • Hill function was fitted to response curves obtained experimentally for WIN55,212 and 2-AG administration.