From Molecular Circuit Dysfunction to Disease: Case Studies in Epilepsy, Traumatic Brain Injury, and Alzheimer's Disease

Abstract

Complex circuitry with feed-forward and feed-back systems regulate neuronal activity throughout the brain. Cell biological, electrical, and neurotransmitter systems enable neural networks to process and drive the entire spectrum of cognitive, behavioral, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits relies on hundreds, if not thousands, of unique molecular interactions. Even single molecule dysfunctions can be disrupting to neural circuit activity, leading to neurological pathology. Here, we sample our current understanding of how molecular aberrations lead to disruptions in networks using three neurological pathologies as exemplars: epilepsy, traumatic brain injury (TBI), and Alzheimer's disease (AD). Epilepsy provides a window into how total destabilization of network balance can occur. TBI is an abrupt physical disruption that manifests in both acute and chronic neurological deficits. Last, in AD progressive cell loss leads to devastating cognitive consequences. Interestingly, all three of these neurological diseases are interrelated. The goal of this review, therefore, is to identify molecular changes that may lead to network dysfunction, elaborate on how altered network activity and circuit structure can contribute to neurological disease, and suggest common threads that may lie at the heart of molecular circuit dysfunction.

Keywords: Alzheimer’s disease; circuits; epilepsy; molecular dysfunction; traumatic brain injury.

Figure 1

The cortico-hippocampal and thalamocortical circuits. Top. Schematic of the cortico-hippocampal circuits. Excitatory pyramidal neurons, brown pyramids; inhibitory interneurons, red circles; synaptic terminals, black circles. DG = dentate gyrus; EC = entorhinal cortex. Bottom. Same as top. Thalamic relay cells, brown circle. Superficial and cortical layers labeled. nRT = thalamic reticular nucleus; TC = thalamocortical; CT = corticothalamic.

Figure 2

Ion channels in microcircuits. Example two neuron microcircuit. Reciprocal connectivity between an excitatory neuron (brown pyramid) and an inhibitory interneuron (red circle). NaChs in the axon initial segment generate action potentials that drive synaptic output onto the connected cell. Calcium channels allow inward current and potassium channels allow outward current flow in the soma of both neuronal subtypes. Nearby astrocytes buffer extracellular potassium via inward flow of potassium ions (see synaptic figure for more roles of astrocytes). For all symbols and their corresponding molecules, see legend.

Figure 3

Synaptic molecules relevant to circuit function. Top. Example excitatory glutamatergic synapse with molecules relevant to synapse and circuit function. Bottom. Example inhibitory GABAergic synapse with molecules relevant to synapse and circuit function. For all symbols and their corresponding molecules, see legend.

Figure 4

Interneuronal sodium channel dysfunction and seizures. Loss of NaChs in the axon initial segment of inhibitory interneurons (1) leads to decreased interneuron activity and reduced inhibition (2). This leads to unconstrained excitation (3) and seizure generation (4). This dysfunction can occur throughout the brain, but here is depicted at the Ca3 to Ca1 synapse (inset).

Figure 5

Thalamocortical circuit disruption. Multiple changes can lead to generation of pathological, seizure-inducing activity in the thalamocortical circuit. These include (1) increased t-type calcium currents in excitatory neurons, (1a) decreased corticothalamic-driven excitation of thalamic interneurons, and (1b) decreased GABA transport by thalamic astrocytes. All these changes lead to increased thalamic excitatory neuron output as depicted by (2) increased rebound bursting. Increased thalamic excitatory neuron output leads to (3) increased circuit hypersynchronization and seizures.

Figure 6

Traumatic brain injury–induced axonal and network damage. (A) Diffuse axonal injury is induced when microtubules (red and blue circles) in the axon are fractured. The presence of the tau protein (blue oval) on microtubules make them able to bend when physical deformation occurs slowly, but makes them brittle when rapid physical strain is put on them (as occurs during TBI). Fracturing of microtubules increases both sodium and calcium influx leading to uncontrolled synaptic output and cell death. (B) Traumatic brain injury disrupts node connectivity and local activity in the brain. In the healthy brain nodes (red circles), or local circuits, are connected to other nodes by their axonal projections (gray lines). This allows efficient network activation and proper local activation (red highlighted areas). After TBI, frank cell loss can occur (loss of red nodes) and axon injury leads to loss of node-to-node connections. This in turns leads to inefficient network activity and reduced local activity (blue highlighted areas).