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

Abstract

The maturation of GABAergic inhibitory circuits is necessary for the onset of the critical period for ocular dominance plasticity (ODP) in the postnatal visual cortex (Hensch, 2005; Espinosa and Stryker, 2012). When it is deficient, the critical period does not start. When inhibitory maturation or signaling is precocious, it induces a precocious critical period. Heterochronic transplantation of GABAergic interneuron precursors derived from the medial ganglionic eminence (MGE) can induce a second period of functional plasticity in the visual cortex (Southwell et al., 2010). Although the timing of MGE transplantation-induced plasticity is dictated by the maturation of the transplanted cells, its mechanisms remain largely unknown. Here, we sought to test the effect of blocking vesicular GABA loading and subsequent release by transplanted interneurons on the ability to migrate, integrate, and induce plasticity in the host circuitry. We show that MGE cells taken from male and female donors that lack vesicular GABA transporter (Vgat) expression disperse and differentiate into somatostatin-and parvalbumin-expressing interneurons upon heterochronic transplantation in the postnatal mouse cortex. Although transplanted Vgat mutant interneurons come to express mature interneuron markers and display electrophysiological properties similar to those of control cells, their morphology is significantly more complex. Significantly, Vgat mutant MGE transplants fail to induce ODP, demonstrating the pivotal role of vesicular GABAergic transmission for MGE transplantation-induced plasticity in the postnatal mouse visual cortex.

Transplanted Cells Are Essential for the Induction But Not the Expression of Cortical Plasticity

“…1C; average ODI, transplanted: mean Ϯ SEM ϭ 0.24 Ϯ 0.03 to Ϫ0.01 Ϯ 0.01, p ϭ 0.01, Wilcoxon signed-rank test, n ϭ 8 mice; control: 0.24 Ϯ 0.05 to 0.18 Ϯ 0.03, p ϭ 0.07, n ϭ 4 mice). Both experimental and control ODIs and OD shifts are consistent with the published data (Southwell et al, 2010;Saiepour et al, 2015;Larimer et al, 2016;Priya et al, 2019) and the absolute OD shift in all transplanted mice were larger than the corresponding measure in any of the control group ( p ϭ 0.004, Wilcoxon rank-sum test). The overall density of transplanted cells in the host primary visual cortex at P46 was 109 Ϯ 9 cells/ mm 2 (Fig.…”

“…If the endogenous inhibitory circuit is compromised by a reduction in GABA release, the normal CP does not start until it is rescued by pharmacological enhancement of GABAergic transmission (Hensch et al, 1998;Fagiolini and Hensch, 2000). Likewise, transplanted interneurons that lack the vesicular GABA transporter (and consequently fail to inhibit the neurons that they contact) fail to induce a second CP (Priya et al, 2019), despite the fact that they appear to develop similarly to wild-type neurons in that they disperse broadly in the host visual cortex, retain normal anatomical and electrophysiological properties, and receive effective synaptic inputs. Their failure to induce a second CP indicates that the output of these cells is essential for the plasticity to be reinstated.…”

Using psychophysical performance to predict short-term ocular dominance plasticity in human adults

“…In fact, anatomophysiologic evidence indicates that the population of GABAergic interneurons in V1 is extremely heterogeneous ( Trachtenberg, 2015 ), comprising at least two very distinct classes of cells ( Maffei, Lambo, & Turrigiano, 2010 ; Priya et al, 2019 ; Scheyltjens & Arckens, 2016 ). Parvalbumin cells ( Scholl, Pattadkal, Dilly, Priebe, & Zemelman, 2015 ) mediate local inhibitory interactions and could mediate the reciprocal inhibition between neighboring ocular dominance cells ( Hensch & Quinlan, 2018 ; Saiepour et al, 2015 ; Trachtenberg, 2015 ).…”

Clustered gamma-protocadherins regulate cortical interneuron programmed cell death

“…As in Larimer et al, 2016 ; Larimer et al, 2017 ; Priya et al, 2019 , host animals were anesthetized and decapitated at 8, 9, 10, 11, or 12 days after transplant. The brain was removed into ice-cold dissection buffer containing (in mM): 234 sucrose, 2.5 KCl, 10 MgSO 4 , 1.25 NaH 2 PO 4 , 24 NaHCO 3 , 11 dextrose, 0.5 CaCl 2 , bubbled with 95% O 2 /5% CO 2 to a pH of 7.4.…”