Tauopathy, which results from the oligomerization of misfolded tau protein in neurons, is a feature present in a number of neurodegenerative diseases and a hallmark of Alzheimer’s Disease (AD). Tau is an important phosphoprotein that regulates the assembly of microtubules, but tauopathy can occur when tau becomes hyperphosphorylated. Phosphorylation prevents tau from binding to tubulin, which results in cytosolic accumulation of tau and eventual oligomerization. This abnormal accumulation of tau leads to the spreading of hyperphosphorylated tau to downstream synaptically connected neurons through an unknown mechanism. In AD, the hippocampus is one of the first brain structures to be affected by tauopathy in humans. According to previous research, tauopathy occurs primarily between principal cells in the hippocampus. The involvement of local inhibitory interneurons in tauopathy and their potential role in AD is more controversial. Previous research suggests that tau pathogenesis primarily affects principal cells; however, given the importance, diversity, and function of interneurons in the hippocampus, it is important to gain a better understanding of the interneuron subtypes that may be impacted by the spread of trans-synaptic tau into the hippocampus. Understanding the involvement of interneurons in trans-synaptic tau transmission is important to understanding neurodegeneration in AD and other neurodegenerative disorders. To investigate this, both male and female genetically-modified mice underwent surgery to examine the trans-synaptic spread of pathogenic tau (EGFP-Tau P301L) from the entorhinal cortex to hippocampal neurons. Histology and imaging analysis of brain sections were performed to examine the hippocampal cells impacted by trans-synaptic spread of tau. Results show that pathogenic tau can trans-synaptically spread from presynaptic neurons in the entorhinal cortex into downstream hippocampal interneurons and also that hippocampal interneurons are capable of trans-synaptically spreading tau. Future studies examining the specific subtypes of hippocampal interneurons vulnerable to trans-synaptic spread of tau will be important for a better understanding of disease progression, which could lead to uncovering new therapeutic targets for neurodegenerative diseases, like AD, which are associated with tauopathy.

<p>The neural code from the inner ear to the brain is dynamically controlled by central nervous efferent feedback to the audio-vestibular epithelium. Although such efference provides the basis for a cognitive control of our hearing and balance, we know surprisingly little about this feedback system. This project has investigated the applicability of a transgenic mouse model, expressing a fluorescent protein under the choline-acetyltransferase (ChAT) promoter, for targeting the cholinergic audio-vestibular efferent neurons in the brainstem. It was found that the mouse model is useful for targeting the vestibular efferents, which are fluorescent, but not the auditory efferents, which are not highlighted. This model enables, for the first time, physiological studies of the vestibular efferent neurons and their synaptic inputs. We next assessed the expression of the potassium channel family Kv4, known to generate transient potassium currents upon depolarization. Such potassium currents are found in auditory efferent neurons, but it is not known whether Kv4 subunits are expressed in these neurons. Moreover, it is not known if Kv4 is present and has a function in the vestibular efferent neurons. Double labelling with anti-ChAT and anti-Kv4.2 or Kv4.3 demonstrates that the Kv4.3 subunits are abundantly expressed in audio-vestibular efferents, thus indicating that this subunit is a large contributor to the excitability and firing properties of the auditory efferent neurons, and most probably also for the vestibular efferent neurons. In addition, we also unexpectedly found a strong expression of Kv4.3 in principal cells of the superior olive, the neurons which are important for sound localization.</p>

The neural code from the inner ear to the brain is dynamically controlled by central nervous efferent feedback to the audio-vestibular epithelium. Although such efference provides the basis for a cognitive control of our hearing and balance, we know surprisingly little about this feedback system. This project has investigated the applicability of a transgenic mouse model, expressing a fluorescent protein under the choline-acetyltransferase (ChAT) promoter, for targeting the cholinergic audio-vestibular efferent neurons in the brainstem. It was found that the mouse model is useful for targeting the vestibular efferents, which are fluorescent, but not the auditory efferents, which are not highlighted. This model enables, for the first time, physiological studies of the vestibular efferent neurons and their synaptic inputs. We next assessed the expression of the potassium channel family Kv4, known to generate transient potassium currents upon depolarization. Such potassium currents are found in auditory efferent neurons, but it is not known whether Kv4 subunits are expressed in these neurons. Moreover, it is not known if Kv4 is present and has a function in the vestibular efferent neurons. Double labelling with anti-ChAT and anti-Kv4.2 or Kv4.3 demonstrates that the Kv4.3 subunits are abundantly expressed in audio-vestibular efferents, thus indicating that this subunit is a large contributor to the excitability and firing properties of the auditory efferent neurons, and most probably also for the vestibular efferent neurons. In addition, we also unexpectedly found a strong expression of Kv4.3 in principal cells of the superior olive, the neurons which are important for sound localization.