Andrew & Patrick’s Neuroblog

Kameyama et al
Neuron 21, 1163-1175, Nov 1998

* NMDA-dependent LTD is associated with Ser845 dephosphorylation
* that Ser845 is normally phosphorylated by PKA
* dephophorylation of postsynaptic PKA substrate is crucial for LTD expression
* injection of cAMP analog: soaks up the PKA and prevents LTD induction!
* PKA inhibitor: produces synaptic depression that occludes homosynaptic LTD
* dephosphorylation of PKA site is one mechanism for NMDAR-dependent homosynaptic LTD expression

Lee at al.
Neuron, 21, 1151-62, Nov 1998

* brief bath application of NMDA to hippocampal slices produces LTD
* LTD is in the CA1 region of the hippocampus
* five properties: sensitive to age, saturable, postsynaptic, reversble, doesn’t change PPF
* chemLTD and homosynaptic LTD are mutually occluding
* common expression mechanism of LTD?
* PSSA: phosphorylation site specific antibodies
* induction of chemLTD induces persistent dephosphorylation of Ser845, but not Ser831
* unexpected role of PKA in postsynaptic modulation of excitatory synaptic transmission.

A new review in Nature Reviews Neuroscience by Kerchner & Nicoll
Nat Rev Neurosci, vol 9, Nov 2008

* silent synapses about in the young brain
* they were discovered in the debate over the presynaptic vs. postsynaptic locus of LTP
* silent synapses are thought to have NMDA receptors but not AMPA receptors
* mechanistic controversy: current model is that unsilencing recruits AMPARs to postsynaptic terminal, so that there are both NMDARs and AMPARs, resulting in a fully functioning synapse
* some synapses are incapable of neurotransmission under basal conditions, wait in a reserv capacity
* silent synapse: unable to mediate synaptic transmission under physiological conditions

Boulanger and Shatz
Nat Rev. Neurosci, Vol 5, July 2004

Key concepts:
* neurons normally express MHC class I molecules in vivo
* MHCI molecules are important for our ability to identify foreigners from self
* recent results: uninjured neurons express both classical and nonclassical MHCI class genes in vivo
* role of neural activity: regulates MHCI experiments
* not quite consistent everywhere, one experiment showed that TTX led to upregulation of MHCI, and another experiment of TTX led to downregulation of MHCI. But those were in different systems, etc.
* need to characterize specific expression profile of MHCI in neurons and in developmental timepts

* need to clarify location, identity, and timing of MHC class I protein expression that is relevant to functional and structural events in neurons
* MHCI receptors that are expressed endogenously in the CNS - PirB is one of them
* there is evidence for a neuronal role of CD3-zeta
* in the immune system: functional TCR-beta transcripts are encoded by loci that have undergone somatic recombination
* but in the brain: the transcripts are products of direct splicing of loci that have not been rearranged

* MHCI-like molecule: FcRn  involved in transport of maternal Ig across fetal intestinal epithelium
* long list of disorders implicating MHCI molecules
* obviously, there are crucial functions of MHCI proteins beyond the immune system
* one hypothesis: affected neurons must express both target antigen and appropriate MHCI molecule to present it
* PND: paraneoplastic neurological degenerative disorders. Primarily affect sites of high MHCI expression
* cellular immune response, e.g. tnf-a and so on, also have critical functions beyond the immune system.
* need to develop objective molecular or biochemical diagnostic criteria
* schizophrenia: a neurodevelopmental disorder, perhaps result of aberrant synaptic organization or loss of connections
* neuronal and immune system MHCI functions may share similar mechanisms.

Title says it all.

* induction of LTP: involves NMDA receptors and rise in postsynaptic intracellular calcium
* rise in Ca is a necessary trigger for LTP
* when the postsynaptic membrane is depolarized, Mg2+ is expelled from the NMDAR channel, allowing calcium to enter the cell as well
* most likely not as simple as a threshold in calcium levels, probably has afferent activity contributions as well
* kinases in LTP PKC, CamKII, Fyn (tyrosine kinase)
* attractive hypothesis: LTP is due to maintenance of increased protein kinase activity - lots of evidence supports this, including the fact that after LTP induction kinase activity levels are elevated for half an hour to an hour.

Nicoll & Malenka, Nature, vol 377, 14 Sept 1995

Key concepts:
* two forms of LTP: NMDAR-dependent and mossy fiber LTP
* NMDAR dependent: relies on rise in postsynaptic calcium levels
* mossy fiber type: independent of NMDARs, requires a rise in presynaptic Ca2+
* mossy fiber LTP is accepted to be expressed presynaptically
* what about site of expression of NMDAR-dependent LTP? Still controversial
* evidence favors postsynaptic for NMDAR-dep, and there’s lots of studies on retrograde messengers that can pass from the postsynapse to presynapse and induce presynaptic changes

(1)
Nature, 14 Sept 1995, Nicoll and Malenka
* activity dependent enhancement of synaptic transmission: LTP
* LTP is observed at many different synapses and many different forms of LTP exist
* mossy fiber LTP and NMDA-dependent LTP are not the same
* different expression mechanisms for different types of LTP
* NMDAR dependent LTP seems to be purely postsynaptic, perhaps with a retrograde messenger.

(2)
Nature, 7 Jan 1993, Bliss and Collingridge
* LTP in the hippocampus: best understood experimental model for looking at learning and memory
* lots of progress made in understanding molecular mechanisms of LTP
* LTP properties: cooperativity, associativity, input-specificity
* cooperativity: intensity threshold for induction
* associativity: weak input can be potentiated if a nearby synapse is potentiated with a strong input
* input specificity: other inputs that are not active don’t potentiate, so specifically the ones that are tetanized are potentiated
* we need to find a mechnistic description of LTP induction requirements. NMDARs are widely thought to be the coincidence detector for presynaptic and postsynaptic activity and critical for expression of LTP.

Esteban et al.
Nat. Neurosci, 6:2, Feb 2003

* PKA phosphorylation of AMPAR subunits contributes to mechanisms underlying plasticity
* state of phosphorylation of GluR1 PKA site: controls channel open time, correlates with changes in synaptic strength
* extensive crosstalk between pathways involved in synaptic plasticity due to enzymes like PKA
* GluR4: PKA can relieve retention
* for GluR4, AMPARs containing GluR4 are incorporated in a manner independent of activity
* PKA activity can induce fast changes in synaptic activity by driving GluR4 incorporation!
* pharmacological activation of PKA leads to increase in CamKII phosphoyrlation of GluR1

Surface Mobility of Postsynaptic AMPARs Tunes Synaptic Transmission
Heine et al., Science, 11 Apr 2008

* AMPARs: mediate fast excitatory synaptic transmission
* lateral diffusion of AMPARs is observed in both intact hippocampi and cultured neurons
* allows fast exchange of desensitized/bound-to-ligand receptors with unbound functional ones in the PSD
* dynamic imaging: showed that AMPARs are not static on the postsynaptic surface. Diffuse rapidly instead at the postsynapse, on the order of micrometers
* crosslinking of surface AMPARs: increases paired pulse depression - makes sense because many AMPARs must now be internalized together - regulates exchange of desensitized receptors for naive receptors
* PPD: similar at other synaptic sites in noninfected neurons, but in neurons expressing the crosslinked GluR1 it is different.
* AMPAR lateral diffusion: influences synaptic transmission at different time scales
* rate of recuperation from synaptic depression: results from recovery of AMPAR desensitization + exchange of desensitized receptors for naive functional receptors
* lateral diffusion of AMPARs affects theoretical recovery rate
* mobility of the AMPARs in the postsynapse affectd by: temp, depol, glutamate, tetanic stimulation
* transmission after activity-dependent processes trigger short and long -term synaptic plasticity.

Lee et al.
Cell, 112, March 7, 2003

Key concepts:
* protein phosphorylation required for induction of many forms of synaptic plasticity
* to test if GluR1 phosphorylation is necessary for spatial memory and synaptic plasticity: mutations in GluR1 phosphorylation sites were done
* changes in presynaptic glutamate release and postsynaptic release are related to LTP and LTD
* both processes (LTP and LTD) are dependent on AMPAR function, but what is the regulatory mechanism for these AMPARs?
* two sites on GluR1 subunit for phosphorylation: serine 831 and serine 845. S831 is phosphorylated by CamKII and PKC, and S845 is phosphorylated by PKA.

* these kinase and phosphatase subsrrates mediate synaptic plasticity!
* changes in ion channel conductance of AMPARs after LTP occur
* key role of GluR1 phosphorylation has been demonstrated in LTD
* other subunits of glutamate receptors: GluR2 plays a critical role in AMPAR internalization
* HFS: high frequency stimulation. Used for LTP induction. This promotes phosphorylation and insertion of GluR1-containing AMPARs into the postsynaptic membrane
* LTD induction by LFS: induces dephosphorylation of GluR1 subunits in AMPARs and results in internalization of the AMPARs
* phosphorylation of two sites (Ser831, Ser845) on GluR1 is critical for NMDAR-dependent LTP and LTD and spatial learning/memory