Dr. Michelle Mynlieff

Ion Channels and Neuronal Function. The overall goal of research in the Mynlieff lab is to understand the cellular and molecular mechanisms that underlie maturation and regulation of neuronal excitability in early brain development. Through gestation and the first year of human life, the excitability of single neurons and of circuits composed of many neurons changes drastically. The increase in excitability in brains of young infants is necessary for the maturation of neuronal circuits but can easily tip the balance into pathological excitatory events such as seizures. Understanding normal excitability is critical to the development of treatments for pathological excitation. Control of single neuron excitability is regulated by ion channels, of which there are many varieties. We have investigated the role of calcium and potassium in neurons isolated from hippocampi of newborn rats and mice. Intracellular calcium acts as a molecular switch affecting many neuronal processes such as neurotransmitter release, enzyme activity, gene expression, and activation of other ion channels. Changes to voltage gated channels to control calcium concentration is a prime means by which neurotransmitters regulate cell function. We have demonstrated that the expression pattern of calcium channels changes as the nervous system undergoes normal maturation. We have also shown that the ubiquitous inhibitory neurotransmitter, γ-amino butyric acid (GABA), enhances L-type calcium channel activity in the early neonatal period by activation of GABAB receptors linked to Gq G-proteins and protein kinase C. Influx of calcium through L-type calcium channels in the early neonatal period upregulates the KCC2 chloride transporter. This upregulation of the chloride transporter is critical for the maturation of the inhibitory circuitry in the brain that leads to the less excitable “adult” brain. Calcium is also necessary to open several potassium channels in neurons. Efflux of potassium through cell surface channels regulates the excitability of neurons, which are potential targets for anti-seizure medication. Currently we are investigating the role of one of these channels, the BK channels, in regulating neuronal excitability on a single cell level in identified interneuron subtypes as well as in an in vitro seizure model. We have demonstrated that BK channels are important in regulating the action potential very early in development and switch to regulating firing rates as hippocampal neurons mature. In recent studies we have been utilizing transgenic mice with labeled interneurons to determine if the role of BK channels in the neonatal period is different in inhibitory interneurons than in the excitatory pyramidal neurons. Changes in potassium channel function in different neurons will have different circuit level outcomes depending on whether the cell is an excitatory pyramidal neuron, a feedforward inhibitory neuron or feedback inhibitory neuron.