6 March 2007. Synaptic plasticity is a contest between long-term potentiation (LTP) and long-term depression (LTD), with the former strengthening synaptic connections and the latter weakening them. Since activation of NMDA-type glutamate receptors induces both LTP and LTD, one might think this tug-of-war is destined to end in a tie. So what determines which has more pull?
A paper in the March 1 Neuron shows that, surprisingly, the enzyme glycogen synthase kinase-3β (GSK3β) appears to sway the balance. Graham Collingridge and colleagues suggest that the kinase plays anchor man on the LTD side, but apparently not very effectively. After induction of LTP, the kinase becomes temporarily inactivated, support for LTD is lost, and LTP comes out on top. This implies that inhibiting GSK3β might boost LTP and depress LTD—good, in a first approximation, for learning and memory.
The finding may have relvance for schizophrenia drug discovery, though any possible role for GSK3β in schizophrenia remains elusive. One putative connection has been made via the enzyme AKT1 (see SRF news story, but this remains unconfirmed. Still, interest remains strong in this molecule, since both antipsychotic and psychotomimetic drugs influence GSK3β activity. (For a recent review focused on possible GSK3β roles in neurodevelopment, see Lovestone et al., 2007).
A pivotal player
To test the role of GSK3β in synaptic plasticity, Collingridge, from the University of Bristol, U.K., and colleagues there and at Canada’s University of British Columbia, Vancouver, and the NIH in Bethesda, Maryland, inhibited the kinase in rat hippocampal slices. Joint first authors Stéphane Peineau and Changiz Taghibiglou found that GSK3β inhibition had no effect on LTP induced by high-frequency stimulation, but completely abolished LTD induced by low-frequency stimulation. The researchers obtained the same result with several GSK3β inhibitors, including the highly selective SB415286, lithium, and kenpaullone, but not with roscovitine, which inhibits the related cyclin-dependent protein kinases. The data indicate that LTD is specifically sensitive to GSK3β inhibition. In support of this, the authors found that during LTD, the kinase is activated by dephosphorylation at serine number 9 (ser9), a post-translational modification. Biochemical assays of GSK3β activity also showed a post-LTD increase of about 30 percent.
It was when the authors tested the duration of GSK3β activation that they found LTP has the opposite effect on the kinase. While ser9 GSK3β phosphorylation declined by about 30 percent 20 minutes after inducing LTD, 20 minutes after induction of LTP, phosphorylation of that residue increased by about 50-60 percent. This observation suggested that LTP might actually inhibit LTD, and when the scientists tested this idea that’s exactly what they found. LTP completely prevented subsequent induction of LTD for as long as 1 hour. One possible role for such regulation might be to “stabilize a synaptic modification over the short term by protecting synapses from the effects of additional NMDA receptor-dependent plasticity until the information can be either consolidated or erased by NMDA receptor-independent mechanisms,” write the authors.
GSK3β has many substrates, and it is unclear how its action on LTD and LTP is regulated. To approach this question, Collingridge and colleagues tested if this mostly cytosolic kinase might be present in synapses. Using immunohistochemistry, they found that it not only occurs on dendritic spines, but also associates with the AMPA receptor subunits GluR1 and GluR2 there. Moreover, NMDA receptor-triggered insertion of AMPA receptors into the plasma membrane appears to be accompanied by a decrease in AMPA-linked GSK3β activity. All told, the work points to GSK3β having some role in the installation or maintenance of AMPA receptors, which may itself prove important for the understanding of schizophrenia (see related SRF news story).—Tom Fagan.
Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JTR, Bortolotto ZA, Wang YT, Collingridge GL. LTP Inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron. 2007 March 1;53:703-717. Abstract