The development and function of the nervous system depend on activity-dependent modification of synaptic connections. Correlated spiking of pre- and postsynaptic neurons can result in persistent strengthening or weakening of synapses, termed long-term potentiation (LTP) or long-term depression (LTD), respectively, depending on the temporal order of pre- and postsynaptic spiking. Our recent results showed that correlated spiking that induces LTP or LTD also leads to bi-directional changes in the intrinsic excitability of the presynaptic neuron and in spatial summation of excitatory postsynaptic potentials (EPSPs) in the postsynaptic dendrite. Furthermore, LTP or LTD induced at one synaptic connection was found to spread to other synaptic sites within the circuit. In the present project, we propose to continue our research on spike timing-dependent plasticity (STDP) of synapses and neuronal properties, using dissociated hippocampal cell cultures and acute hippocampal and cortical slices. In Part I, we will further examine the properties of STDP of glutamatergic and GABAergic synapses in hippocampal circuits, the cellular mechanisms underlying the expression of LTP/LTD, and the factors that modulate the time windows of pre- and postsynaptic spiking for the LTP/LTD induction. In Part II, we will examine the effects of correlated on the intrinsic excitability of both pre- and postsynaptic neurons in cortical slices and on spatial and temporal summation of EPSPs in the dendrites of CA1 pyramidal cells in hippocampal slices. In Part III, we will examine the non-local nature of synaptic modifications following LTP/LTD induction by correlated activity, i.e., the heterosynaptic effects and the spread of potentiation/depression within the neural circuits in hippocampal cultures or in acute hippocampal and cortical slices. Together, these studies address several fundamental issues concerning STDP of neural circuits and explore new territories of neuronal plasticity. The information and insights obtained will contribute to our understanding of the development and plasticity of the nervous system. ? ?
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