A Hybrid Model to Explore How a Hippocampal CA1 Neuronal Network Is Affected by Faulty Molecules of an Intraneuronal CREB Signaling Network

Analysis of intraneuronal signaling networks using systems biology approaches provides insights on how various molecules within each neuron may affect the behavior of the neuron under normal and pathological conditions. However, memory formation, learning and cognition are sophisticated functions of the human brain that not only depend on intraneuronal molecules and systems, but also emerge from the collective behavior of neurons in complex neuronal networks and the interneuronal processes among them. Therefore, understanding psychiatric and mental disorders where learning, memory or cognition are impaired, requires a hybrid modeling approach where both intraneuronal and interneuronal processes are included. In this paper, a hybrid model is introduced where a hippocampal CA1 neuronal network is considered, together with an intraneuronal signaling network that regulates the CREB (cAMP Response Element-Binding) protein. CREB is a transcription factor that is highly involved in cognitive and executive function of the human brain. Upon using the hybrid intraneuronal/interneuronal model, together with fault diagnosis analysis, we determine how neuronal excitability in the context of a neuronal network is affected, when there is one faulty - mutated or dysfunctional - molecule, or two concurrently faulty molecules. The hybrid approach allows to classify molecules into different classes, depending on how much they affect a neuronal network, when they are faulty. This has important applications in target discovery, since analysis of the hybrid model reveals which molecules or pairs of molecules result in substantial deviation from the normal network behavior, when they are faulty. Such molecules may be considered as proper targets, to develop effective therapeutics.