Genetic Elimination of GABAergic Neurotransmission Reveals Two Distinct Pacemakers for Spontaneous Waves of Activity in the Developing Mouse Cortex

Abstract

Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves.

SamuROI, a Python-Based Software Tool for Visualization and Analysis of Dynamic Time Series Imaging at Multiple Spatial Scales

“…Specific uses of macro-scale imaging include the spatial and temporal spread of spontaneous activity in brain slices (Easton et al, 2014) or interregional synchrony in vivo (Busche et al, 2015). …”

Regulation of Spontaneous Propagating Waves in the Embryonic Mouse Brainstem

“…At stages later than P6, the chloride gradient has matured and GABA is inhibitory to waves, as the blocker picrotoxin induces waves. Interestingly, at intermediate stages (P1–P4), both initiating systems co-exist (Easton et al, 2014). Unlike retina and cortex, the receptor profile for SA in the hindbrain does not change over the developmental window of SA, with the exception of a slight contribution of NE receptor signaling at E13.5 (Hunt et al, 2006a).…”

Neuronal activity controls the development of interneurons in the somatosensory cortex

“…The piriform cortex and septal nucleus are pacemaker locations, and the wave initiation sites are highly correlated to the position of GABAergic neurons (Conhaim et al, 2011). There are both GABAergic and glutamatergic fractions of waves that propagate from ventral structures; although, the glutamatergic fraction seems to preferentially propagate to the neocortex, particularly as postnatal development proceeds (Easton et al, 2014). It is possible that both thalamic and other subcortical patterns interact to produce the oscillatory patterns observed in the developing somatosensory cortex.…”