Fig 2: Transplanted PV+ interneurons contribute to the inhibitory gain control on native pyramidal cells. A, Representative traces recorded from a native pyramidal cell at various levels of current injection with and without simultaneous activation of nearby transplanted PV+ cells. In the absence of photostimulation, 40-pA current injection elicited single AP over a 200-ms period (red trace). When current injection was increased to 100 and 200-pA, the multiple spikes were elicited, and the frequencies were 19.6 Hz (brown trace) and 37.4 Hz (black trace), respectively. In the presence of photostimulation, 40-pA current injection failed to bring the cell over threshold. On 100- and 200-pA current injection, the spike frequencies were 17.7 and 35.4, respectively. B, C, The I-F curves under various conditions obtained from the same cells shown in A. Linear regression was employed to fit the data. The slope factor for the control condition is 0.118 (open squares, r 2 = 0.978), and that with photostimulation is 0.110 (open circles, r 2 = 0.982). After the application of 100 µM gabazine, the slope factors are 0.127 (closed squares, r 2 = 0.972) and 0.127 (closed circles, r 2 = 0.992) for conditions with and without photostimulation, respectively. In the absence of gabazine, photostimulation shifts the I-F curve to the right by 10.6 pA, whereas it only shifts the curve by 4.4 after the addition of gabazine. D, In the absence of gabazine, the normalized slope factor with photostimulation is 0.989 ± 0.090 and is not significantly different from that under control condition (paired t test, n = 8, p = 0.907). In the presence of 100 µM gabazine, the normalized slope factor with photostimulation is 1.013 ± 0.029 compared with that without photostimulation. There is no statistical significance between these two conditions (paired t test, n = 6, p = 0.399). E, On average, activating transplanted Parv+ cells shift the I-F curve of pyramidal cells by 12 ± 3.8 pA (n = 8). This effect can be significantly reduced by 100 µM gabazine (-2.4 ± 2.6 pA, n = 6; two sample t test, p = 0.013). The shift observed in the presence of gabazine is not different from zero (one-sample t test, n = 6, p = 0.252).

Fig 3: Altered interneuron subtype proportions upon Grin1-ablation. (A) Integrated UMAP visualization of 12 subtypes of MGE-derived interneurons obtained from neocortex (nCX) and hippocampus (HPC) of Grin1wt/wt and Grin1fl/fl mice. UMAP represents the following numbers of MGE-derived interneurons from Grin1wt/wt and Grin1fl/fl, respectively: 5624 (nCX.WT) and 1387 (nCX.NULL); 2998 (HPC.WT) and 2309 (HPC.NULL). 3 and 2 independent biological replicates of the scRNAseq assay from Grin1wt/wt and Grin1fl/fl, respectively. (B) Violin plot showing the distribution of expression levels of well-known representative cell-type-enriched marker genes across the 12 interneuron subtypes. (C) Violin plot from both genotypes indicating the expression of Grin1 in the cardinal of MGE-derived interneuron subtypes. (D) UMAP representation colored by brain-region, highlighting the differential enrichments of cells (brown arrows) within interneuron subsets in Grin1wt/wt and Grin1fl/fl from nCX and HPC. (E) Stacked-barplots representing the proportions of recovered cell numbers within (Ei), pooled cardinal MGE subtypes, (Eii), SST subtypes; (Eiii), PVALB subtypes, and (Eiv), NGFC subtypes in Grin1-WT and Grin1-null from neocortex or hippocampus.x2, Chi-square test of proportions; ns, not significant.

Fig 4: Effects of 5-HT and the 5-HT2A/2C antagonist ketanserin (Ket; 10 µm) on OFCPV cell Iholds in cocaine-naive rats. A, Time course of mean (±SEM) inward currents caused by bath application of 5-HT (20 µm, horizontal gray bar) alone, or during treatment with ketanserin in male Pvalb-iCre rats (N, n = 7, 13). Inward currents with 5-HT alone were observed in the majority of OFCPV neurons in males and females (22/28 cells, 11 rats, 78.6%). B, Time course of mean (±SEM) inward currents caused by bath application of 5-HT alone, or during application of ketanserin in female Pvalb-iCre rats (N, n = 4, 11). C, Mean (±SEM) outward 5-HT-induced currents were observed in a minority of male OFCPV cells (4/28 cells, 14.3%). D, Mean maximal effects of 5-HT alone, or during application of ketanserin in OFCPV neurons from male and female Pvalb-iCre rats. The effects of 5-HT under control and ketanserin conditions were obtained by averaging data across the final 3 min of the 5-HT application periods shown in A, B. Note that although the magnitudes of the 5-HT-induced inward currents did not differ between male and female OFCPV neurons in the control condifontstion, they were significantly blocked by ketanserin only in female Pvalb-iCre rats (two-way ANOVA, sex × treatment interaction F(1,27) = 8.671, p = 0.0066; Tukey’s post hoc comparisons, male 5-HT vs ketanserin p > 0.9999, female 5-HT vs ketanserin, **p = 0.0007, male vs female ketanserin, *p = 0.0116). ns, not significant.

Fig 5: Pcdhg function is not required for the survival of PV cINs after the period of programmed cell death.(A) Mutant mice with loss of Pcdhg in SST or PV cells were generated by crossing conditional Pcdhgfcon3 mice to mice carrying Cre under Sst (SstCre) or Pvalb (Parvalbumin, PVCre). The conditional Ai14 line was used to fluorescently label SST or PV cells. (B) Photographs of coronal sections of the primary visual cortex (V1) of P30 SstCre; Ai14;Pcdhg+/+ (Pcdhg WT, top left) and SstCre;Ai14;Pcdhgfcon3/fcon3 (Pcdhg mutant, bottom left) mice. Scale bars, 50 µm. (C) Quantifications of the density of tdTomato+ cINs in V1 cortex of Pcdhg WT (black) and Pcdhg mutant (magenta) SstCre;Ai14 mice at P30 (Mann-Whitney test, **p=0.0286, n = 4 mice of each genotype). (D) Photographs of coronal sections of V1 in PVCre;Ai14;Pcdhg+/+ (Pcdhg WT, top right) and PVCre;Ai14;Pcdhgfcon3/fcon3 (Pcdhg mutant, bottom right) mice at P60. Scale bars, 50 µm. (E) Quantifications of the density of tdTomato+ cIN in V1 cortex of Pcdhg WT and Pcdhg mutant PVCre;Ai14 mice at P60-100 (Mann-Whitney test, p=0.4206,n = 5 mice of each genotype). Figure 6—source data 1.Analysis of PV and SST- derived cINs at P30 in controls and Pcdhg mice.