Karl Kandler, Ph.D.
University of Pittsburgh
School of Medicine
October 18, 2010

Tuning Up Inhibition

Moving away from the specification of neurotransmitters reveals another striking structure and function relationship. How neurons decide which connections to form and break has important implications for effective brain function. For example, during mammalian development, neuronal connections form in the portions of the brain responsible for sound localization. How these neurons connect to one another serves as the structural basis for hearing. Dr. Kandler's presentation to the Volen Center explored the molecular mechanisms through which these processes occur. As one of his tools Dr. Kandler makes use of "knockout" mice — animals in which a specific gene has been deleted.

Accurate hearing depends on precisely organized and fine-tuned neuronal connectivity in the brain. During development, this organization emerges gradually through mechanisms that are still poorly understood. To gain more insight into these mechanisms, Dr. Kandler's lab has been investigating the processes that are involved in the establishment of a precisely organized inhibitory pathway in the mammalian primary sound localization system.

The Kandler lab has demonstrated that an inhibitory pathway, the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO), is refined by the silencing of most initial connections and the strengthening of maintained connections. Interestingly, this reorganization occurs while MNTB-LSO synapses not only release glycine, but also co-release GABA and even glutamate. Glutamate released from MNTB terminals can activate postsynaptic NMDA receptors, which significantly contribute to local calcium responses in aspiny LSO neurons. To test whether this transient glutamate co-release is important for the refinement of the MNTB-LSO pathway, the Kandler lab has investigated the development of the MNTB-LSO pathway in mice missing the vesicular glutamate transporter 3 (VGLUT3) gene. These mice demonstrate a lack of glutamate release from MNTB terminals, while glutamate release from other terminals in the LSO is undisturbed. These results demonstrate a significant impairment in the refinement of the MNTB-LSO pathway in VGLUT3 knockout mice, indicating that glutamate co-release is a novel and important synaptic mechanism in the refinement of the inhibitory MNTB-LSO pathway. Due to the wide expression of VGLUT3 in a variety of other non-glutamatergic circuits, glutamate co-release may also be involved in the plasticity of non-glutamatergic synapses elsewhere in the brain.