How do neuronal circuits form in the developing brain?

Mis-wiring of neuronal circuits during early life is one of the major causes of neurological disorders, including autism and schizophrenia. The Lu lab is interested in how activity-dependent processes during brain development fine-tune the establishment of neural circuits and how neural activity affect neural circuit wiring and cognitive behaviors. Specifically, we are interested in exploring the role of the metabotropic glutamate receptor 5 (mGluR5), a group 1 metabotropic glutamate receptor. mGluR5 mutations have been identified in some ADHD and schizophrenic patients. We employ genetic tools in an attempt to understand the contribution of mGluR5 signaling in specific neuronal populations to sensory circuit formation, synaptic function/plasticity, and behavior. We are also exploring the role of the endogenous cannabinoid (endocannabinoid) system in fetal brain development and investigating how prenatal cannabis exposure affects brain development and later behaviors. Understanding the effects of endocannabinoids during neural circuit formation will not only shed light on normal brain development and function but will also allow us to assess endocannabinoid-based therapies and the effects of cannabis use on the developing fetus.

 

How is a healthy brain maintained and what causes neurons to die?

Dementia, such as Alzheimer’s disease, is caused by neurodegeneration.  Proper brain function requires an active maintenance program to sustain neuronal health. When neuroprotective mechanisms are weakened, environmental stressors detrimentally impact the nervous system, predisposing it to neuronal dysfunction and degeneration. We and others have identified NMNAT2 (nicotinamide mononucleotide adenylyl transferase 2) as a neuroprotective protein key to maintaining neuronal integrity throughout life. NMNAT2 abundance is significantly reduced in Alzheimer’s Disease brains, and increased NMNAT2 expression in neurodegenerative animal models reduces neurodegeneration. Elucidating how NMNAT2 provides neuroprotection will allow us to develop therapeutic interventions to protect neurons against pathological insults and slow down the rates of cognitive decline in dementia patients.