Title

Development of Electrical Excitability in the Human Cerebral Cortex during the Second Trimester of Gestation

Date of Completion

January 2010

Keywords

Biology, Neurobiology

Degree

Ph.D.

Abstract

The development of the human cerebral cortex is a highly orchestrated series of events including neuronal proliferation, migration, and differentiation. The establishment of adult patterns of neuronal connectivity and function in the human brain does not begin with sensory experience, but rather with spontaneous electrical activity prior to birth. Since electroencephalographic (EEG) recordings cannot be used to analyze cellular and molecular mechanisms, our understanding of human cortical development and the emergence of early electrical activity has been highly dependent on animal studies. Significant differences in cortical volume, duration of development, and complexity make direct comparisons between human cortex and animal models very difficult. The goal of this dissertation was to obtain direct recordings from human cortical neurons during the second trimester of gestation (16 – 22 gw), and characterize the physiological aspects of brain development. First we asked where, in what cortical zone, and when, in what gestational week, human neurons acquire the ability to generate nerve impulses (i.e. action potentials). As early as 16 gestational weeks, a relatively small population of cortical plate neurons (27%) was able to generate sodium action potentials upon direct current injection. Neurons located in the subplate exhibited the highest level of cellular differentiation, as judged by their ability to fire repetitive action potentials. At 19 gestational weeks, a fraction of human cortical plate and subplate neurons possess βIV spectrin-positive axon initial segments populated with voltage-gated sodium channels (PanNav). Second, we searched for signs of spontaneous electrical activity. In each human specimen tested we found a substantial number of cortical subplate neurons that exhibited robust spontaneous (unprovoked) activity, comprised of action potentials riding atop plateau depolarizations, similar to cortical UP and DOWN states found in the adult neocortex during sleep. Thirdly, we investigated the cellular mechanisms of electrical oscillations in the prenatal cerebral cortex. Experimental data obtained in 11 human subjects indicated that spontaneous activity in human subplate neurons was not mediated by glutamatergic, GABAergic, or glycinergic synaptic transmission, but rather through connexin 26 and 32 based hemichannels (not gap junctions). Taken together these data provides the very first physiological characterization of the human fetal cortex 4 months before birth. ^