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MSc Exit Seminar – Annik Yalnizyan-Carson (Richards lab)

September 21, 2015 @ 10:10 am - 10:40 am

MSc Exit Seminar

Monday September 21st, 10:10 am – Ramsay Wright Building, Rm. 432

Annik Yalnizyan-Carson (Richards lab) 

“Modeling Ca2+-Dependent Regulation of KCC2 Phosphorylation as a Mechanism for Inhibitory Synaptic Plasticity”


Inhibitory synaptic transmission in the mammalian central nervous system is chiefly mediated by the neurotransmitter γ-aminobutryic acid (GABA). The primary receptor for GABA is the Cl- -permeable ionotropic GABAA receptor. In mature neurons, maintenance of low intracellular Cl- by the K+-Cl- co-transporter KCC2 results in Cl- influx and subsequent hyperpolarization of the cell upon GABA binding. Sustained repetitive activation of pre- and postsynaptic neurons with a fixed temporal separation has been shown to alter the strength of synaptic signaling. These changes occur via Ca2+ -dependent mechanisms which are sensitive to precise pre- and post-synaptic spike times, a phenomenon known as spike timing-dependent plasticity (STDP). At GABAergic synapses, plasticity induction using “coincident” intervals between pre- and post-synaptic spikes (i.e. intervals < ±20ms) leads to depolarizing shifts in the GABA reversal potential (EGABA) and, upon subsequent stimulation of GABAergic synapses, the driving force for Cl- is reduced and hyperpolarization is diminished. The precise molecular mechanisms for this change have not been fully resolved. It has been shown that inhibitory STDP principally involves Ca2+ influx via specific voltage-gated Ca2+ channels (VGCCs), namely the L- and T-type VGCCs. Furthermore, the Ca2+-sensitive kinase PKC and phosphatase calcineurin have been shown to control the phosphorylation state of KCC2 at key residues involved in membrane stabilization and transport efficacy. It has been hypothesized that Ca2+ influx via L- and T-type VGCCs can affect the level of activation of PKC and calcineurin, thereby effecting the phosphorylation state of KCC2, and hence, its Cl- extrusion capacity. This thesis presents a computational model to explore Ca2+-dependent dephosphorylation of KCC2 as a plausible mechanism for the depolarizing shift in EGABA seen in inhibitory STDP. Using a kinetic model of KCC2 phosphorylation in a biophysically realistic neuron model, we demonstrate that dephosphorlation of KCC2 triggered by T-type mediated Ca2+ influx can cause a depolarizing shift in EGABA that is sensitive to precise spike times. These results suggest that Ca2+-dependent dephosphorylation of KCC2 is a plausible molecular mechanism for inhibitory STDP. This model predicts that T-type VGCCs should be particularly important for triggering changes in KCC2 phosphorylation in response to coincident activity.

Ramsay Wright is a wheelchair accessible building.



September 21, 2015
10:10 am - 10:40 am
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Ramsay Wright Building, Room 432
25 Harbord St.
Toronto, ON M5S 3G5 Canada