Modeling Changes in Inhibitory Signaling in Visual Processing of Lewy Body Dementia Patients

Modeling Changes in Inhibitory Signaling in Visual Processing of Lewy Body Dementia Patients Introduction Lewy Body Dementia (LBD) is the second most common type of dementia and is often characterized by visual hallucinations (VH), a symptom frequently used to distinguish it from other forms of dementia during diagnosis. ● VH in LBD are associated with a decrease in choline acetyltransferase (ChAT) activity in cholinergic neurons in the Nucleus Basalis of Meynert (NBM), the area of the brain responsible for sending acetylcholine throughout the cerebral cortex. ChAT enzymes are in charge of synthesizing acetylcholine, so as a result of their decreased activity, there is a widespread loss of acetylcholine projection to different areas of the brain and particularly to the visual cortex in LBD patients. ● Acetylcholine normally acts as a vasodilator, opening blood vessels to allow blood to flow through more easily. Hypoperfusion in the visual cortex occurs in LBD patients due to a lack of acetylcholine. ● The lack of blood flow to these regions of the brain causes glucose hypometabolism, meaning that the neurons in the brain are deprived of the ATP they need to function properly (Fig. 1). ● It is believed that as a result, these patients experience problems with GABAergic neurotransmission, which involves sending inhibitory signals. This lack of inhibition throws off the inhibition-excitation balance needed to properly process visual stimuli. Results Discussion To model the effects of a decrease in GABAergic neurotransmission, we decreased the synaptic weight of the inhibitory connection at 10% intervals and analyzed the effects it had on the pyramidal cell’s spiking patterns. ● Without the necessary inhibitory signals being sent to their OFF surround, the pyramidal cells in our new model began to become overexcited. In the context of visual processing, this could mean that pyramidal cells trying to process visual stimuli, such as a flashing circular spot, wouldn’t be able to accurately process the exact location of the light and would instead also fire in areas near the spot, making it difficult to clearly see the stimuli. This could explain many of the visual deficits LBD patients experience that include difficulties in recognizing objects and extracting concrete shapes. ● Furthermore, the disinhibited pyramidal cells may even fire in the absence of any visual stimuli, producing the visual hallucinations experienced by many LBD patients. Fig. 4 Healthy Network with firing rate 9.55 Hz. Our models and results hope to make contributions to crafting new methods of early diagnoses, improving current treatments, and creating novel medicines. Fig. 5 Network of 50% disinhibition with firing rate 10.73 Hz. Fig. 6 Network of 100% disinhibition with firing rate 11.89 Hz. Fig. 1 Hypometabolism in LBD patients as shown by a FDG-PET scan. Fig. 7 Firing rates of pyramidal cells in response to disinhibition. Methods To model the effects of the imbalance in inhibitory and excitatory signals, we used a NEURON model of the dorsal lateral geniculate nucleus (dLGN) developed by Heiberg, Hagen, Haines, and Einevoll (2016). This area of the brain is a relay station located in the thalamus, meaning that it takes input from retinal ganglion cells and sends signals to the visual cortex for higher-level processing. Fig. 2 Synaptic connections in the model circuit. In our model, the dLGN was comprised of two different types of cells: interneurons (IN) and relay cells (RC). To specifically model the changes in GABAergic neurotransmission seen in LBD patients, we chose to focus on the inhibitory signal being sent from the axon of the interneurons to the relay cells located in the same layer. Our model was built to look into how this inhibitory signal modulated the receptive-field properties of relay cells by increasing their center-surround suppression in response to a flashing circular spot. We hypothesized that when the strength of the inhibitory connections was decreased, this center-surround suppression would become defective. Unfortunately, we were not able to successfully get this model code to work due to continuous issues with module versions. Instead, we analyzed the results gathered from another model to predict what would’ve been the outcome from our original model. Our alternative model was a single-cell model of a pyramidal cell in layer 5 of the visual cortex developed by Bahl (2012) to run with the NEURON-Python interface. This pyramidal cell received excitatory and inhibitory signals through modeled synapses. The timing of these signals was dictated by an input spike train generated from normal firing patterns of relay cells in the dLGN without the effects of interneurons, a piece of data we were able to gather from our original model. Excitatory signals in this model represented direct signaling from relay cells in the dLGN and were sent without delay to the pyramidal cell. Inhibitory signals represented signaling from local inhibitory cells and were sent at a 3 millisecond delay to represent the time it would take for a signal from the dLGN to be sent to a pyramidal cell, then to a local inhibitory cell, and then back to the pyramidal cell we were modeling. Fig 3. Synaptic connections in the alternate model. ● Like other forms of dementia, an early diagnosis would be very beneficial in making the most out of available treatments. Understanding the formation of VH in LBD can be helpful in recognizing patterns of developing VH or other associated symptoms, which can be helpful in developing early diagnoses for LBD patients. ● A better understanding of the mechanisms of VH can also be helpful in optimizing existing form of treatment for dementia, such as ChEIs like Donepezil and Rivastigmine. ● Though a bit far-reaching, our model is also a step towards developing a new form of treatment. With a better understanding of the role GABAergic neurotransmission plays in the production of VH, the next step is to test medication aimed at adjusting the inhibition/excitation balance that is altered by a lack of inhibitory signals in LBD patients. Similar to SSRIs that block serotonin reuptake channels, medication that prevents GABA from being reabsorbed or broken down could potentially be useful as a form of treatment.