Periodic Reporting for period 4 - SensoNMDA (Impact of NMDA receptor diversity in sensory information processing)
Berichtszeitraum: 2021-06-01 bis 2021-11-30
The human brain is a remarkable computation device whose function relies mostly in the activity of networks of neurons communicating with each other via specialized connections denominated synapses. The presence of an extremely elevated number of neurons and a complex connectivity diagram among the different cellular elements are clear contributors to such unique functional capabilities. However, is now particularly obvious that the functional properties of synapses are not uniform but rather variable across synapses in the brain. The functional consequence of such diversity is not clear but is thought to increase computational power.
We are presently investigating how diversity in synaptic function contributes to information processing in the primary somatosensory cortex. Understanding the cellular mechanisms involved in information process by the brain is a fundamental question in neuroscience and a better knowledge of the human brain is expected to help in the development of new therapeutical approaches to correct brain dysfunction associated with neurological diseases and disorders.
We have focused our attention in the glutamate receptor NMDA, whose activity is essential for correct brain function and has been implicated in key brain functions like learning and memory. We have observed that the density and biophysical properties of synaptic NMDAR are particular variable among local GABAergic interneurons in primary somatosensory cortex and we are presently carrying in vivo experiemnts to investigate the impact of such diversity in the computation of sensory information.
We are presently investigating how diversity in synaptic function contributes to information processing in the primary somatosensory cortex. Understanding the cellular mechanisms involved in information process by the brain is a fundamental question in neuroscience and a better knowledge of the human brain is expected to help in the development of new therapeutical approaches to correct brain dysfunction associated with neurological diseases and disorders.
We have focused our attention in the glutamate receptor NMDA, whose activity is essential for correct brain function and has been implicated in key brain functions like learning and memory. We have observed that the density and biophysical properties of synaptic NMDAR are particular variable among local GABAergic interneurons in primary somatosensory cortex and we are presently carrying in vivo experiemnts to investigate the impact of such diversity in the computation of sensory information.
To tackle the proposed objectives, we used an array of genetic, optogenetic and pharmacological tools in combination with imaging and electrophysiological approaches. Specifically, we have identified vesicular zinc as a selective modulator of synaptic plasticity and dendritic non-linearities in the primary somatosensory cortex through its actions on synaptic NMDARs (Morabito et al., 2022, Cell. Reports, in press). Our results suggest that such a mechanism should have an important role in the function of the neocortex.
We were also able to observe that neocortical interneurons express functional NMDARs with unusual biophysical properties. We observed that such an atypical NMDA receptor are selectivity expressed in somatostatin-positive interneurons. In vivo recordings revealed that the new signaling mechanism is essential for the neuronal representation of spontaneous behaviors. The study was submitted for publication. The original finding opens a new perspective on the cellular mechanisms that govern neocortical function and reveals a previously unknown molecular target that can be used to develop new therapies for neurological diseases.
We were also able to observe that neocortical interneurons express functional NMDARs with unusual biophysical properties. We observed that such an atypical NMDA receptor are selectivity expressed in somatostatin-positive interneurons. In vivo recordings revealed that the new signaling mechanism is essential for the neuronal representation of spontaneous behaviors. The study was submitted for publication. The original finding opens a new perspective on the cellular mechanisms that govern neocortical function and reveals a previously unknown molecular target that can be used to develop new therapies for neurological diseases.
The new cellular elements now reported reveal previously unknown modulatory systems in cortical function. We expect that by the end of the project to have identified a new pathway by which NMDARs and endogenous modulators of NMDAR function (zinc) impacts the process of sensory information.