Shaping of neural activity by homeostatic plasticity

Abstract

The positive-feedback nature of Hebbian plasticity can cause instability in neuronal networks and drive them to a state of hyperactivity or hypoactivity. Homeostatic plasticity is a crucial counter mechanism that maintains the excitability of the nervous system by modulation of synaptic strengths and membrane conductances. The regulation of synaptic strengths often occurs through various presynaptic modifications that affect the release of neurotransmitters. To understand how synaptic transmission and synaptic plasticity are affected during presynaptic homeostasis, we developed a biophysically-detailed, spatially-explicit, and stochastic model of the CA3-CA1 presynapse to describe the most significant presynaptic homeostatic modifications, such as changes in voltage-dependent calcium channel (VDCC) expression and placement and readily releasable pool (RRP) size. We chose the hippocampal CA3-CA1 synapse for our investigations since it’s a highly plastic synapse important for learning and memory. Through simulations of presynaptic activity leading to vesicular release, we examined how changes in the expression and organization of VDCCs affect the probability of neurotransmitter release. We investigated the influence of presynaptic homeostatic changes on short-term plasticity (STP), given that STP has an essential role in information transmission and optimizing energetic expenditure during synaptic transmission. Our results suggest that short-term plasticity is altered during homeostatic modifications. We explored the further impact of these modifications on information transfer and energy efficiency during vesicular release. The data suggest that homeostatic changes in VDCC expression and RRP size do not affect the transfer of information but affect the specific cost of information. We also provided an explanatory framework for enhanced miniature excitatory postsynaptic current (mEPSC) frequency observed after the suppression of activity. According to our results, an increase in the readily-releasable pool size causes a proportional increase in mEPSC frequency and only partly explains the observed increase. The large magnitude of changes in mEPSC frequency can be explained by a plausible increase in cytosolic basal calcium concentration. Overall, our study investigates how presynaptic homeostatic modifications influence synaptic strength, short-term plasticity, and the transmission of information at the synapses. The changes observed in short-term plasticity suggest that homeostatic plasticity might have a dynamic role in shaping neural activity rather than merely serving as a stabilizing mechanism.