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

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”

Abstract

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 GABA_A 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 (E_GABA) 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 E_GABA 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 E_GABA 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.