Hippocampal Interneurons and Their Role in the Control of Network Excitability
- Chris J. McBain, PhD, Head, Section on Cellular and Synaptic Physiology
- Kenneth Pelkey, PhD, Staff Scientist
- Ramesh Chittajulla, PhD, Senior Research Fellow
- Gulcan Akgul, PhD, Postdoctoral Fellow
- Michael Craig, PhD, Postdoctoral Fellow
- James D'Amour, PhD, Postdoctoral Fellow
- Vivek Madahavan, PhD, Postdoctoral Fellow
- Jason Wester, PhD, Postdoctoral Fellow
- Megan Wyeth, PhD, Postdoctoral Fellow
- Xiaoqing Yuan, MSc, Biologist
- Steven Hunt, Biologist
- Daniela Calvigioni, BSc, Graduate Student
- Geoff Vargish, BS, Graduate Student
Cortical and hippocampal local-circuit GABAergic inhibitory interneurons are ‘tailor-made’ to control Na+- and Ca2+-dependent action potential generation, regulate synaptic transmission and plasticity, and pace large-scale synchronous oscillatory activity. The axons of this diverse cell population make local, usually short-range projections (some subpopulations project their axons over considerable distances) and release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) onto a variety of targets. A mounting appreciation of the roles played by interneurons in several mental health conditions such as epilepsy, stroke, Alzheimer’s disease, and schizophrenia have placed this important cell type center stage in cortical circuit research. Our main objective is to understand the developmental programs that regulate their integration into cortical circuits and how both ionic and synaptic mechanisms regulate the activity of cortical neurons at the level of small, well defined networks. To this end, we use a variety of electrophysiological, immunohistochemical, molecular, and genetic approaches in both wild-type and transgenic animals. Over the past few years, we have continued our study on the differential mechanisms of glutamatergic and GABAergic synaptic transmission and plasticity within the hippocampal formation and the modulation of voltage- and ligand-gated channels expressed in inhibitory neurons. We also incorporate genetic approaches to unravel the embryogenesis and development of hippocampal interneurons and the circuits in which they are embedded. We are particularly interested in discovering the rules that dictate coordinated protein expression in nascent interneuron subpopulations as they migrate and integrate into the developing cortical circuit.
Inhibitory interneurons differentially contribute to spontaneous network activity in the developing hippocampus dependent on their embryonic lineage.
Spontaneously generated network activity is a hallmark of developing neural circuits and plays an important role in the formation of synaptic connections. In the rodent hippocampus, this activity is observed in vitro as giant depolarizing potentials (GDPs) during the first postnatal week. Interneurons importantly contribute to GDPs owing to the depolarizing actions of GABA early in development. While they are highly diverse, cortical interneurons can be segregated into two distinct groups based on their embryonic lineage from either the medial or caudal ganglionic eminences (MGE and CGE). There is evidence suggesting that CGE–derived interneurons are important for GDP generation; however, their contribution relative to those from the MGE has never been directly tested. We optogenetically inhibited either MGE– or CGE–derived interneurons in a region-specific manner in mouse neonatal hippocampus in vitro. In the CA1 region of the hippocampus, where interneurons are the primary source of recurrent excitation, we found that those from the MGE strongly and preferentially contributed to GDP generation. Furthermore, in dual whole-cell patch recordings in the neonatal CA1, MGE interneurons formed synaptic connections to and from neighboring pyramidal cells at a much higher rate than those from the CGE. The MGE interneurons were commonly perisomatic-targeting, in contrast to those from the CGE, which were dendrite-targeting. We also found that inhibiting MGE interneurons in CA1 suppressed GDPs in the CA3 region and vice versa; conversely, they could also trigger GDPs in CA1 that propagated to CA3 and vice versa. Our data demonstrate a key role for MGE–derived interneurons in both generating and coordinating GDPs across the hippocampus.
Persistent inhibitory circuit defects and disrupted social behavior following in utero exogenous cannabinoid exposure
Placental transfer of Δ9-tetrahydrocannabinol (THC) during pregnancy has the potential to interfere with endogenous cannabinoid (CB) regulation of fetal nervous system development in utero. We examined the effect of maternal CB intake on mouse hippocampal interneurons, focusing largely on cholecystokinin-expressing interneurons (CCK-INTs), a CB subtype-1 receptor (CB1R)–expressing neuronal population prominent throughout development. Maternal treatment with THC or the synthetic CB1R agonist WIN55,212-2 (WIN) produced a significant loss of CCK-INTs in the offspring. Further, residual CCK-INTs in animals prenatally treated with WIN displayed reduced dendritic complexity. Consistent with these anatomical deficits, pups born to CB–treated dams exhibited compromised CCK-INT–mediated feedforward and feedback inhibition. Moreover, pups exposed to WIN in utero lacked constitutive CB1R–mediated suppression of inhibition from residual CCK-INTs and displayed altered social behavior. Our findings add to a growing list of potential cell/circuit underpinnings that may underlie cognitive impairments in offspring of mothers who abuse marijuana during pregnancy.
Additional Funding
- Megan Wyeth was funded by a Postdoctoral Research Associate (PRAT) Fellowship.
- Jason Wester was funded by an NINDS Intramural National Research Service Award (NRSA)
Publications
- Wester J, McBain CJ. Inhibitory interneurons differentially contribute to spontaneous network activity in the developing hippocampus dependent on their embryonic lineage. J Neurosci 2016;36:2646-2662.
- Vargish GA, Pelkey KA, Yuan X, Chittajallu R, Collins D, Fang C, McBain CJ. Persistent inhibitory circuit defects and disrupted social behavior following in utero exogenous cannabinoid exposure. Mol Psychiatry 2017;22(1):56-67.
- Peng S, Xu J, Pelkey KA, Chandra G, Zhang Z, Bagh MB, Yuan X, Wu L-G, McBain CJ, Mukherjee AB. Suppression of agrin-22 production and synaptic dysfunction in Cln1 (-/-) mice. Ann Clin Transl Neurol 2015;2:1085-1104.
Collaborators
- Matthew Colonnese, PhD, The George Washington University School of Medicine & Health Sciences, Washington, DC
- Roderick McInnes, PhD, Lady Davis Research Institute, McGill University, Toronto, Canada
- Anil Mukherjee, PhD, Section on Developmental Genetics, NICHD, Bethesda, MD
- Michael Salter, PhD, Centre for the Study of Pain, Hospital for Sick Children, Toronto, Canada
- Paul Worley, PhD, The Johns Hopkins University, Baltimore, MD
Contact
For more information, email mcbainc@mail.nih.gov or visit https://neuroscience.nih.gov/Faculty/Profile/chris-mcbain.aspx.
