🧠Computational Neuroscience Unit 4 – Synaptic Transmission & Plasticity

Key Concepts

• Synapses are specialized junctions that allow neurons to communicate with each other and with other cells
• Neurotransmitters are chemical messengers released by presynaptic neurons that bind to receptors on postsynaptic cells
• Synaptic plasticity refers to the ability of synapses to strengthen or weaken over time in response to activity and experience
  • Includes long-term potentiation (LTP) and long-term depression (LTD)
• Hebb's postulate states that synapses are strengthened when presynaptic and postsynaptic neurons are simultaneously active
• Synaptic transmission involves the release of neurotransmitters from synaptic vesicles into the synaptic cleft
• Postsynaptic receptors can be ionotropic (directly open ion channels) or metabotropic (activate second messenger cascades)
• Computational models of synaptic transmission aim to simulate and predict synaptic behavior using mathematical equations and algorithms

Synaptic Structure and Function

• Synapses consist of a presynaptic terminal, a synaptic cleft, and a postsynaptic membrane
• Presynaptic terminals contain synaptic vesicles filled with neurotransmitters and voltage-gated calcium channels
• The synaptic cleft is a narrow gap between the presynaptic and postsynaptic membranes that allows for rapid diffusion of neurotransmitters
• Postsynaptic membranes contain receptors that bind to specific neurotransmitters and trigger changes in the postsynaptic cell
• Synapses can be excitatory (increase the likelihood of postsynaptic firing) or inhibitory (decrease the likelihood of postsynaptic firing)
  • Determined by the type of neurotransmitter released and the receptors present on the postsynaptic cell
• Synaptic efficacy refers to the strength of the synaptic connection and can be modulated by various factors (neurotransmitter release probability, receptor density, etc.)

Neurotransmitter Release and Reception

• Action potentials arriving at the presynaptic terminal trigger the opening of voltage-gated calcium channels
• Calcium influx causes synaptic vesicles to fuse with the presynaptic membrane and release neurotransmitters into the synaptic cleft
• Neurotransmitters diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic membrane
• Ionotropic receptors directly open ion channels, leading to rapid changes in postsynaptic membrane potential
  • Examples include AMPA and NMDA receptors for glutamate, and GABAA receptors for GABA
• Metabotropic receptors activate second messenger cascades, leading to slower and longer-lasting changes in postsynaptic cell function
  • Examples include mGluRs for glutamate and GABAB receptors for GABA
• Neurotransmitters are cleared from the synaptic cleft by reuptake into the presynaptic terminal or by enzymatic degradation

Electrical Properties of Synapses

• Synaptic transmission can be modeled as a change in conductance across the postsynaptic membrane
• Excitatory postsynaptic potentials (EPSPs) result from the opening of cation channels and depolarize the postsynaptic membrane
• Inhibitory postsynaptic potentials (IPSPs) result from the opening of anion channels or the closing of cation channels and hyperpolarize the postsynaptic membrane
• The magnitude and duration of postsynaptic potentials depend on factors such as the number of activated receptors and the membrane time constant
• Synaptic integration refers to the summation of multiple postsynaptic potentials over time and space
  • Can be linear (additive) or nonlinear (multiplicative or saturating)
• Dendritic spines are small protrusions on dendrites that receive synaptic input and compartmentalize biochemical signaling

Types of Synaptic Plasticity

• Short-term plasticity occurs on a timescale of milliseconds to minutes and includes facilitation, depression, and augmentation
  • Facilitation is an increase in synaptic strength due to residual calcium in the presynaptic terminal
  • Depression is a decrease in synaptic strength due to depletion of readily releasable vesicles
• Long-term plasticity occurs on a timescale of hours to days and includes LTP and LTD
  • LTP is a persistent increase in synaptic strength induced by high-frequency stimulation or coincident pre- and postsynaptic activity
  • LTD is a persistent decrease in synaptic strength induced by low-frequency stimulation or asynchronous pre- and postsynaptic activity
• Spike-timing-dependent plasticity (STDP) is a form of long-term plasticity that depends on the relative timing of pre- and postsynaptic spikes
  • Pre-before-post spiking leads to LTP, while post-before-pre spiking leads to LTD
• Homeostatic plasticity maintains the overall activity of a neuron or network within a stable range
  • Includes synaptic scaling, which adjusts the strength of all synapses on a neuron in response to changes in activity

Computational Models of Synaptic Transmission

• Hodgkin-Huxley model describes the electrical properties of neurons using a set of differential equations
  • Can be adapted to model synaptic conductances and postsynaptic potentials
• Kinetic models of synaptic transmission use rate equations to describe the binding and unbinding of neurotransmitters to receptors
  • Examples include the Destexhe-Mainen-Sejnowski model for AMPA and NMDA receptors
• Phenomenological models capture the essential features of synaptic transmission without detailed biophysical mechanisms
  • Examples include the alpha function and the double exponential function for modeling synaptic conductances
• Network models incorporate multiple synaptic connections between neurons to study the emergent properties of neural circuits
  • Can be used to investigate the role of synaptic plasticity in learning and memory

Learning and Memory at the Synaptic Level

• Synaptic plasticity is thought to be a cellular mechanism for learning and memory
• Hebbian learning, based on Hebb's postulate, strengthens synapses when pre- and postsynaptic activity is correlated
  • Underlies associative learning and the formation of cell assemblies
• Non-Hebbian learning, such as heterosynaptic plasticity and neuromodulation, can modify synaptic strength independently of pre- and postsynaptic activity
• Synaptic consolidation refers to the stabilization of synaptic changes over time
  • Involves the synthesis of new proteins and the restructuring of synaptic connections
• Synaptic tagging and capture hypothesis proposes that synapses undergoing plasticity are "tagged" and can capture plasticity-related proteins synthesized in response to strong stimulation
• Engrams are hypothesized to be the physical substrates of memories, potentially encoded by specific patterns of synaptic weights

Research Methods and Techniques

• Electrophysiology techniques, such as patch-clamp recording and voltage-clamp, are used to measure synaptic currents and potentials
  • Can be performed in vitro (brain slices) or in vivo (anesthetized or awake animals)
• Optogenetics allows for the selective activation or inhibition of specific neuronal populations using light-sensitive ion channels (opsins)
  • Can be used to study the role of specific synaptic connections in behavior and cognition
• Calcium imaging uses fluorescent indicators to measure changes in intracellular calcium concentration, a proxy for neuronal activity
  • Can be used to monitor synaptic transmission and plasticity in large populations of neurons
• Electron microscopy provides high-resolution images of synaptic ultrastructure
  • Can be used to study changes in synaptic morphology associated with plasticity
• Molecular biology techniques, such as Western blotting and immunohistochemistry, are used to study the expression and localization of synaptic proteins
• Computational modeling and simulation are used to test hypotheses and generate predictions about synaptic function and plasticity
  • Can be constrained by experimental data and used to guide further experiments