Research in Focus is a series that highlights Neurobiology faculty members’ papers in peer-reviewed journals.
Linda Overstreet-Wadiche, Ph.D., professor in the department of Neurobiology, and vice chair for Faculty Affairs and Development, was published in the Journal of Neuroscience for her recent paper “T-Type Ca2+ Channels Mediate a Critical Period of Plasticity in Adult-Born Granule Cells.”
The dentate gyrus is an interesting brain region where neurogenesis, or the production of new neurons from stem cells, continues throughout adulthood. These newly formed neurons have beneficial effects on cognition because they exhibit a high degree of synaptic plasticity, that is, they can change the strength of their synaptic connections in response to new experiences.
Recent work from the Wadiche lab addressed why young adult-born neurons exhibit so much plasticity compared to the surrounding older neurons. Understanding this question can potentially point to new therapies to enhance brain plasticity in conditions where neurogenesis is lost, such as aging and neurodegenerative diseases.
To better understand the importance of this study, we sat down with Wadiche to discuss her research findings.
Q: Can you describe the key findings of your recent publication?
The adult hippocampus contains stem cells that continuously generate new neurons. Our work addresses the long-standing question of why young adult-born neurons have synapses that exhibit more plasticity compared to surrounding pre-existing mature neurons.
Prior work had proposed that young neurons exhibit more plasticity because they have less GABAergic inhibition, whereas other work suggested that high intrinsic excitability conferred by T-type Ca2+ channels allowed young neurons to show more plasticity. We used a mouse model that allows us to record neurons of different ages to show that the key lies in the activity of T-type Ca2+ channels. GABAergic inhibition suppresses plasticity in all neurons, but T-type Ca2+ channels empower young neurons to overcome inhibition, giving them a competitive edge in activity-driven synaptic plasticity.
What inspired you to pursue this area of research?
I’ve been fascinated by synaptic plasticity ever since I learned that changes in the strength of synaptic connections between neurons is the primary way that the brain learns and remembers. It’s what inspired me to go to graduate school to study neuroscience. But since I was a postdoc, my research has focused on other fundamental properties of neurons in the hippocampus, including adult-born neurons and GABAergic interneurons.
This project was really initiated by my graduate student, William Kennedy, who joined my lab with the specific goal of studying synaptic plasticity in adult-born neurons. I must give him credit for bringing the lab back to the roots of what originally inspired my interest in neuroscience.
What were some of the biggest challenges you faced during this project?
The biggest challenge for this project was the technical approach that William used to perform the experiments. We typically use a single-cell electrophysiological recording technique called whole-cell recording to monitor synaptic responses and measure how they change over time. This is the most common approach to study the electrical properties of individual neurons. But this approach disrupts the native intracellular components of the neuron that could affect the results, especially in studies of inhibition and long-term synaptic plasticity. So, William used a non-invasive technique called perforated-patch recording. It is technically very challenging, but William mastered it and even ended up writing a methods chapter for a textbook about it.
Were there any surprising or unexpected results in your research?
We first replicated prior results by others showing that young adult-born neurons exhibit a high propensity for long-term potentiation (LTP), a form of synaptic plasticity. This is important to show the reproducibility of the approaches that we use and allow us to investigate the mechanisms underlying this high degree of LTP.
The most surprising finding was that even though young neurons show greater synaptic plasticity than surrounding older neurons, the older neurons still retain the potential for plasticity mediated by T-type calcium channels. Our results suggest that this channel activity is not completely lost but rather it is suppressed by intracellular signaling cascades. This observation was only possible because William was using the challenging, non-invasive approach of perforated patch recording mentioned above.
How does your discovery advance our understanding of the brain and its functions?
We made several important advances. First, we showed that low synaptic inhibition is the not reason that young neurons exhibit a high degree of synaptic plasticity. This clarifies a long-standing question in the field and illustrates the importance of T-type calcium channel activity in young neurons that enables them to overcome the effect of inhibition. Most importantly, showing that mature neurons (the vast majority of neurons in this brain region) retain the capacity to exhibit plasticity by upregulation of T-type calcium channel activity provides a potential therapeutic target for treating disorders where neurogenesis is lost. There is extensive evidence that ongoing neurogenesis provide beneficial effects for many hippocampal-dependent cognitive functions, but neurological diseases are often accompanied by a loss of these highly plastic young neurons. So, understanding the properties that allow young neurons to enhance hippocampal function, and knowing how that function can be restored in mature neurons, could be a strategy to enhance hippocampal function in the many conditions where neurogenesis is lost.