Mechanisms and Function of Neuromodulation
Neurons are finely tuned to extract computationally relevant features from synaptic inputs. This process is influenced heavily by neuromodulators, which can transiently retune neuronal processing by altering the properties of the membrane receptors and channels involved in synaptic transmission and cell excitability. Our lab is interested in understanding the mechanisms by which neuromodulators control excitability and synaptic integration, and how the dysfunctions in these mechanisms contribute to neurological disorders, including psychiatric disease and addiction.
Current projects include:
Understanding the distribution and function of dopamine receptors in prefrontal networks:
D1/D5 receptors have been known to regulate transmission at glutamatergic inputs in prefrontal cortex. We show just how unique their regulation is in this paper. In contrast to many other types of presynaptic neuromodulators, which filter synaptic activity depending on the frequency of transmission, D1/D5 receptors regulate PFC inputs independent of the history of activity. This allows dopamine to fine-tune the relative volume of different inputs.
D3 receptors are enriched in limbic systems, including frontal cortex. We have identified a population of layer 5 pyramidal cells in which D3 receptors regulate excitability. In addition, we applied machine learning techniques in Matlab and in Python to improve classification accuracy of this novel pyramidal neuron subtype. Further, we have shown that D3 receptors act through non-canonical GPCR pathways. We are currently investigating how these systems are engaged by antipsychotic medications and drugs of abuse.
We are investigating how GABAergic systems develop and are regulated in prefrontal circuits. We have focused on how serotonergic systems regulate the overall function and integrative properties of fast spiking interneurons.
Furthermore, we have been studying functional development of prefrontal inhibition, which is, at certain synapses, remarkably delayed.
The role of SCN2A in autism and childhood epilepsy
Dysfunction in SCN2A, which encodes the neuronal sodium channel NaV1.2, is strongly linked to autism and several forms of childhood epilepsy of differing severity. NaV1.2 is enriched at the axon initial segment, and plays a role in neuronal excitability. The lab is working to understand how different mutations in SCN2A result in different childhood disorders and to determine if and when one can intervene to restore proper SCN2A function in rodent models. We work closely with both the Sanders and Ahituv Lab at UCSF on these projects.
The genetics and physiology of SCN2A in autism and early-onset seizures (Simons VIP Connect/YouTube)
"In this webinar, Drs. Kevin Bender and Stephan Sanders will detail recent advances in our understanding of how different mutations in SCN2A contribute to the different forms of epilepsy, including benign infantile seizure and epileptic encephalopathy, and how these mutations contrast with those that contribute to autism. We will further discuss how the distribution of NaV1.2 within neurons develops over the first few years of life, and how these changes affect neuronal function. This development has important implications for understanding these disorders and in designing potential therapies in the future."