## Biological Basis of the Model Code The provided code is part of a computational neuroscience model simulating **recurrent spreading depolarizations**—a phenomenon typically observed in pathological conditions such as brain injury, migraines, or stroke. These spreading depolarizations involve waves of profound, sustained depolarization across neuronal and glial tissues, resulting in significant disruptions in ion homeostasis, neuronal activity, and potentially contributing to secondary injury processes. ### Key Biological Components #### Ion Currents and Channels The model includes several ion currents and channels that are pivotal for neuron and astrocyte electrophysiological behavior: 1. **Fast Na+ Current (ina)**: This reflects the rapid depolarization of neurons due to the influx of Na+ through voltage-gated sodium channels. 2. **Persistent Na+ Current (inap)**: This contributes to sustained depolarization and is crucial in maintaining the depolarized state during spreading depolarizations. 3. **K+ Current (ik)**: This regulates repolarization by allowing K+ ions to exit the cell, and involves delayed rectifier K+ channels that are important for setting the membrane potential back to rest after depolarization. 4. **NMDA Receptor-Mediated Currents (inmda)**: NMDA receptors are ionotropic glutamate receptors playing a role in calcium influx, synaptic plasticity, and excitotoxicity. They contribute to excitatory neurotransmission and Ca2+ dynamics. 5. **Cl- Leak Current (icl)**: This models the passive flow of chloride ions, contributing to maintaining resting membrane potential and cell volume regulation. 6. **Na-K ATPase Pump (ipump, ipumpa)**: Critical for maintaining ion gradients across the membrane by actively pumping 3 Na+ out and 2 K+ into the neuron, utilizing ATP. #### Ion Homeostasis The model encompasses differential equations representing changes in ion concentrations over time within the neuron and its surroundings: - _Ke_, _Ki_, _Nae_, _Nai_, _Cle_, _Cli_, and _Ca2+_ dynamics are fundamental for neuronal firing and signaling, as well as astrocytic regulation, reflecting interactions across neuron-glial networks. #### Astrocyte Functionality - **Astrocytic Na+ and K+ Currents**: Astrocytes are modeled with their own sets of ion channels and transporters, underlining their role in buffering extracellular ion concentrations and potentially releasing signaling molecules (like glutamate). - **Na-glutamate Co-transporter (inagl)**: Represents the glutamate uptake by astrocytes, which is crucial for synapse clearing and neurotransmitter cycling. #### Glutamate Dynamics The inclusion of the glutamate transporter describes the build-up and clear-out of extracellular glutamate concentrations, an element essential to both normal synaptic transmission and excitotoxicity during sustained depolarizations. #### Calcium Dynamics - **Intracellular Ca2+ Management**: The model simulates calcium transport mechanisms across the membrane, including SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase) pumps, release from the endoplasmic reticulum, and leak channels, reflecting their contribution to signaling and excitotoxic processes. ### Summary Overall, the model targets a complex interplay of neuronal and glial processes involved in spreading depolarizations, capturing key mechanisms of ion channel dynamics, neurotransmitter cycling, and cellular homeostasis. This provides insights into how these cellular processes contribute to neuronal dysfunction during widespread pathological brain activity.