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Developmental biology - Brain

How Memories Form

How do cells generate memories?...


The dentate gyrus of the hippocampus is where memories form. It's also one of only two areas in an adult's brain where new neurons continuously form. Our brain cortex generates signals that are either sensory or related to spatial awareness and sends them to the dentate gyrus where they combine into a unique memory.

Location of Dentate Gyrus

In order to compute all the signals the dentate gyrus receives, cell interaction must be electrically 'quiet'. Therefore granule cells, the principal neurons in the dentate gyrus, are kept inhibited by a strong signal placing them in a state of low excitability. However, newborn granule cells are highly excitable, and only enter a quiet state as they mature.

Little was known about these mechanisms before the research by Linda Overstreet-Wadiche PhD and Jacques Wadiche PhD, at the University of Alabama (UAB). Their work describes the key role G proteins mediate between cell signals and how a late maturation in granule cells occurs. This, their most recent study is published in the Journal of Neuroscience.
"Our goal was to characterize the function, maturation and sources of this signaling pathway, so that in the future it can be manipulated for therapeutic purposes."

Linda Overstreet-Wadiche PhD, Associate Professor, University of Alabama (UAB), Birmingham, Alabama, USA.

G Protein Act As Molecular On - Off Switch

Sodium Channel - Voltage Gate

A brief visual explanation on YouTube of ion channels.

G proteins appear numerous times in Nobel Prize-winning research as ion channels in the cell membrane regulate ion flow in or out of a cell. This flux of ions generates electrical currents across the cell membrane controlling the excitability of each neuron.
Overstreet-Wadiche and colleagues found that intact G protein signaling is required for low granule cell excitability. They also found that a potassium channel called GIRK or G protein-activated inward rectifying potassium channel, is constantly active in mature dentate granule cells keeping neurons less excitable by lowering that cells' membrane potential to exchange ions.

Researchers observed how 10 to 12 day old granule cells, don't have functional GIRK channels. Not until about three weeks will functional GIRK channels appear and respond to G protein signals via a cell receptor called GABA B. GABA in mammals, short for gamma-aminobutyric acid, is our chief inhibitory neurotransmitter. When inhibitory neurons release GABA, it binds to receptors on targeted neurons and inhibits that circuit.

GIRK appears to lower excitability of mature dentate granule cells in two ways. First - through constantly active GIRK channels that reduce resting cell membrane potential for ion exchanges and excitability. Second - via inhibitory neurons that release GABA. By phasing activation of GIRK signals, GABA crosses the synapse and enters the dentate granule cell activating GABA-B-receptor to G-protein signaling.
"The dentate gyrus is critical for controlling the flow of neural activity through the hippocampus, a gatekeeping function important not only for normal cognition, but also for suppressing seizure activity.

"We have shown how a well-known signaling pathway makes a particularly strong contribution to suppressing excitability in the [dentate gyrus] region, answering a longstanding question about why these neurons have such a low resting membrane potential compared to other neurons."


Linda Overstreet-Wadiche PhD.

Abstract
Sparse neural activity in the dentate gyrus is enforced by powerful networks of inhibitory GABAergic interneurons in combination with low intrinsic excitability of the principal neurons, the dentate granule cells (GCs). Although the cellular and circuit properties that dictate synaptic inhibition are well studied, less is known about mechanisms that confer low GC intrinsic excitability. Here we demonstrate that intact G protein-mediated signaling contributes to the characteristic low resting membrane potential that differentiates mature dentate GCs from CA1 pyramidal cells and developing adult-born GCs. In mature GCs from male and female mice, intact G protein signaling robustly reduces intrinsic excitability, whereas deletion of G protein-activated inwardly rectifying potassium channel 2 (GIRK2) increases excitability and blocks the effects of G protein signaling on intrinsic properties. Similarly, pharmacological manipulation of GABAB receptors (GABABRs) or GIRK channels alters intrinsic excitability and GC spiking behavior. However, adult-born new GCs lack functional GIRK activity, with phasic and constitutive GABABR-mediated GIRK signaling appearing after several weeks of maturation. Phasic activation is interneuron specific, arising primarily from nNOS-expressing interneurons rather than parvalbumin- or somatostatin-expressing interneurons. Together, these results demonstrate that G protein signaling contributes to the intrinsic excitability that differentiates mature and developing dentate GCs and further suggest that late maturation of GIRK channel activity is poised to convert early developmental functions of GABAB receptor signaling into GABABR-mediated inhibition.

Authors: Jose Carlos Gonzalez, S. Alisha Epps, Sean J. Markwardt, Jacques I. Wadiche and Linda Overstreet-Wadiche.


Acknowledgements
Support was provided by National Institutes of Health grants NS064025, NS065920 and NS075162.

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Aug 20, 2018   Fetal Timeline   Maternal Timeline   News   News Archive




A sagittal view of white matter fiber in the human brain obtained using Diffusion Spectral Imaging, a technique explored by the NIH Human Connectome Project and advanced by BRAIN Initiative projects. Image Credit: National Institutes of Healtth.


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