Synaptic plasticity pathways

As discussed in the previous section, the motivation is to model the interaction between electrical activity in neurons and the synaptic proteome. This example (currently at https://collab.humanbrainproject.eu/#/collab/2184/nav/303192) shows how interactions between a number of ions, proteins and second messengers can be modeled.

Proteins involved

The full list of “agents” in the molecule_definitions.ka file is:

 1 %agent: ca(x)
 2 %agent: Glu(x)
 3 %agent: NMDA(x, b0, b1, state~R~RA~RA2~d1~d2~2f~2s~o, type~A~B, mgb)
 4 %agent: mg(x)
 5 %agent: AMPA(x, loc~m~b~t, ser845~u~p, ser831~u~p, b1, b2, b3, b4, state~c0~c1~c2~c3~c4~d1~d2~d3~d4~o1~o2~o3~o4)
 6 %agent: PMCA(x, cam)
 7 %agent: NCX(x)
 8 %agent: IMCBP(x)
 9 %agent: CaB(h1, h2, h3, m1)
10 %agent: CaM(site1, c1, c2, n1, n2)
11 %agent: CaMKII(A, B, D, cam, sub, phos, Thr286~u~p, Thr305~u~p)
12 %agent: NG(cam)
13 %agent: CaN(cam, sub, m1, m2)
14 %agent: AC1(cam)
15 %agent: AC8(cam, camLoc~none~nLobe~cLobe)
16 %agent: PDE1B(x, cam, phos~u~p)
17 %agent: PDE4(x, pka, phos~u~p)
18 %agent: cAMP(x)
19 %agent: PKA(x, A1, B1, A2, B2, type~f~r~c) #full/regulatory/catalytic
20 %agent: I1(x, thr35~u~p)
21 %agent: PP1(x, i1)

Rules

These lines from the molecule_definitions.ka demonstrate how binding cAMP to PDE4 in an unphosphorylated state:

'PDE4 binding cAMP' PDE4(x, phos~u), cAMP(x) -> PDE4(x!1, phos~u), cAMP(x!1) @ 'PDE4cAMPk+'
'PDE4 unbinding cAMP' PDE4(x!1, phos~u), cAMP(x!1) -> PDE4(x, phos~u), cAMP(x) @ 'PDE4cAMPk-'
'PDE4 destroys cAMP' PDE4(x!1, phos~u), cAMP(x!1) -> PDE4(x, phos~u) @ 'PDE4cAMPcat'

These lines demonstrate phosphorylation of PDE4 by PKAc:

'PKAc phosphorylating PDE4' PKA(x!1, type~c), PDE4(x!1, phos~u) -> PKA(x, type~c), PDE4(x, phos~p) @ 'PKAPDE4cat'
'4Ca-CaM-CaN dephosphorylating PDE4 phos' CaN(cam!2, sub!1),
CaM(site1!2, c1!_, c2!_, n1!_, n2!_), PDE4(x!1, phos~p) ->
  CaN(cam!2, sub), CaM(site1!2, c1!_, c2!_, n1!_, n2!_), PDE4(x, phos~u) @ 'CaNPDE4cat'

Results

The output of the simulation is shown below:

../../../_images/simulation-results.png