Heterosynaptic mechanisms driving elevated synaptic inhibition and plasticity impairments following ischemia.

About This Grant

Heterosynaptic mechanisms driving elevated synaptic inhibition and plasticity impairments following cardiac arrest GABAergic inhibitory synapses innervate pyramidal neurons and are crucial for controlling neuronal firing and excitability. Synaptic inhibition profoundly influences the efficacy of excitatory synaptic transmission, by regulating synaptic plasticity, dendritic Ca2+-transients and dendritic integration. Upscaling of inhibitory synapses is a homeostatic mechanism that occurs in response to persistent increases in neuronal excitability. Ischemia drives excitotoxic increases glutamatergic transmission that can result in CA1 pyramidal cell loss and long-term impairments in long-term potentiation. We have recently published that at chronic timepoints that there is a upscaling of GABAergic inhibitory synapses in surviving neurons through postsynaptic clustering of GABAA receptors and their scaffold, gephyrin. We hypothesize that ischemia engages increases GABAA postsynaptic structure and function that is mediated by CAMKII and results in increased inhibition relative to excitation. We also hypothesize that GABAergic upscaling is maladaptive and ultimately contributes to impaired excitatory synaptic. In this project, we will explore the mechanisms that mediate strengthening of GABAergic synapses and whether increased inhibition dampens glutamatergic synaptic transmission and plasticity. To evaluate this hypothesis, we will use an in vivo rodent model of cardiac arrest to induce global cerebral ischemia and perform electrophysiology, imaging and biochemistry to evaluate changes in inhibitory and excitatory synapse structure and function. We will use pharmacological, genetic and optogenetic manipulations of synaptic receptors and intracellular signaling pathways to target changes in synaptic function. These studies will elucidate mechanisms of cognitive impairment following cerebrovascular injury.