Development and long-term integration of MGE-lineage cortical interneurons in the heterochronic environment

Abstract

Interneuron precursors transplanted into visual cortex induce network plasticity during their heterochronic maturation. Such plasticity can have a significant impact on the function of the animal and is normally present only during a brief critical period in early postnatal development. Elucidating the synaptic and physiological properties of interneuron precursors as they mature is key to understanding how long-term circuit changes are induced by transplants. We studied the development of transplant-derived interneurons and compared it to endogenously developing interneurons (those that are born and develop in the same animal) at parallel developmental time points, using patch-clamp recordings in acute cortical slices. We found that transplant-derived interneurons develop into fast-spiking and non-fast-spiking neurons characteristic of the medial ganglionic eminence (MGE) lineage. Transplant-derived interneurons matured more rapidly than endogenously developing interneurons, as shown by more hyperpolarized membrane potentials, smaller input resistances, and narrower action potentials at a juvenile age. In addition, transplant-derived fast-spiking interneurons have more quickly saturating input-output relationships and lower maximal firing rates in adulthood, indicating a possible divergence in function. Transplant-derived interneurons both form inhibitory synapses onto host excitatory neurons and receive excitatory synapses from host pyramidal cells. Unitary connection properties are similar to those of host interneurons. These transplant-derived interneurons, however, were less densely functionally connected onto host pyramidal cells than were host interneurons and received fewer spontaneous excitatory inputs from host cells. These findings suggest that many physiological characteristics of interneurons are autonomously determined, while some factors impacting their circuit function may be influenced by the environment in which they develop. Transplanting embryonic interneurons into older brains induces a period of plasticity in the recipient animal. We find that these interneurons develop typical fast-spiking and non-fast-spiking phenotypes by the end of adolescence. However, the input-output characteristics of transplant-derived neurons diverged from endogenously developing interneurons during adulthood, and they showed lower connection rates to local pyramidal cells at all time points. This suggests a unique and ongoing role of transplant-derived interneurons in host circuits, enabling interneuron transplant therapies.

An increase in neural stem cells and olfactory bulb adult neurogenesis improves discrimination of highly similar odorants

“…In summary, both morphometric and electrophysiological analyses (Figs 3 and EV3), together with our previous assessment of molecular markers (Fig 2), confirmed that the maturation, integration, and activity of 4D-derived granule cells were in all aspects similar to that of physiologically generated neurons. This contrasts the differences observed in endogenous vs. graft-derived interneurons following transplantation of neural precursors (Larimer et al, 2017) suggesting that supernumerary neurons by our 4D manipulation in NSC not only are similar in cell-intrinsic properties but also have no competitive disadvantage compared to endogenous neurons. This in turn distinguishes our approach from previous studies assessing the role of neurogenesis in olfaction upon manipulations changing the intrinsic properties of the neurons themselves and/or their niche.…”

“…C 3D reconstruction of multi-channel confocal stacks acquired from a RFP + apical dendrite of a granule cell showing co-localization with the pre-and post-synaptic markers VIAAT (granule neuron) and gephyrin (mitral cell), respectively (magnification shown in insets). This contrasts the differences observed in endogenous vs. graft-derived interneurons following transplantation of neural precursors (Larimer et al, 2017) suggesting that supernumerary neurons by our 4D manipulation in NSC not only are similar in cell-intrinsic properties but also have no competitive disadvantage compared to endogenous neurons. Inset shows a representative RFP + synapse (out of > 10 analyzed from 4D + mice).…”

Vesicular GABA Transporter Is Necessary for Transplant-Induced Critical Period Plasticity in Mouse Visual Cortex

“…We categorized all recorded neurons as either fast spiking (spike rate Ͼ90 Hz in response to DC current injections of 2ϫ rheobase) or non-fast spiking (Fig. 7E) (Larimer et al, 2017). Neither input resistance ( Fig.…”

“…Cells derived from the MGE and CGE migrate to specific laminae in the developing neocortex and differentiate into distinct types of GABAergic interneurons (Anderson et al, 1999(Anderson et al, , 2001Parnavelas, 2000;Wichterle et al, 2001;Nery et al, 2002;Butt et al, 2005). MGE-and CGE-derived interneurons retain the ability to disperse and functionally integrate when transplanted into both the juvenile and adult brain, receiving excitatory and inhibitory inputs and forming inhibitory synapses onto host neurons (Wichterle et al, 1999;Alvarez-Dolado et al, 2006;Southwell et al, 2010;Larimer et al, 2016Larimer et al, , 2017. Modifying synaptic inhibition by MGE-derived interneuron transplantation provides a unique opportunity for the treatment of disorders that are linked to interneuron dysfunction or circuit hyperexcitability (Southwell et al, 2014;Tyson and Anderson, 2014;Spatazza et al, 2017).…”

Interneuron transplantation: a prospective surgical therapy for medically refractory epilepsy

“…As different forms of inhibition play distinct roles in neural circuit excitatory-inhibitory balance and seizure formation, future studies may be directed toward examining the disease-modifying effects of subtype-restricted donor populations. 12,34,69 Further advances may also allow for monitoring transplant cellular dispersion and controlling transplant activity in the recipient. For example, bioluminescence imaging of transplant populations, 3 or MRI, 39 could allow noninvasive visualization of transplant dispersion and engraftment.…”