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. 2023 Nov 17;13(11):1598.
doi: 10.3390/brainsci13111598.

Increased Inhibition May Contribute to Maintaining Normal Network Function in the Ventral Hippocampus of a Fmr1-Targeted Transgenic Rat Model of Fragile X Syndrome

Leonidas J Leontiadis  1 , George Trompoukis  1 , Panagiotis Felemegkas  1 , Giota Tsotsokou  1 , Athina Miliou  1 , Costas Papatheodoropoulos  1
Affiliations

Increased Inhibition May Contribute to Maintaining Normal Network Function in the Ventral Hippocampus of a Fmr1-Targeted Transgenic Rat Model of Fragile X Syndrome

Leonidas J Leontiadis et al. Brain Sci. .

Abstract

A common neurobiological mechanism in several neurodevelopmental disorders, including fragile X syndrome (FXS), is alterations in the balance between excitation and inhibition in the brain. It is thought that in the hippocampus, as in other brain regions, FXS is associated with increased excitability and reduced inhibition. However, it is still not known whether these changes apply to both the dorsal and ventral hippocampus, which appear to be differently involved in neurodegenerative disorders. Using a Fmr1 knock-out (KO) rat model of FXS, we found increased neuronal excitability in both the dorsal and ventral KO hippocampus and increased excitatory synaptic transmission in the dorsal hippocampus. Interestingly, synaptic inhibition is significantly increased in the ventral but not the dorsal KO hippocampus. Furthermore, the ventral KO hippocampus displays increased expression of the α1GABAA receptor subtype and a remarkably reduced rate of epileptiform discharges induced by magnesium-free medium. In contrast, the dorsal KO hippocampus displays an increased rate of epileptiform discharges and similar expression of α1GABAA receptors compared with the dorsal WT hippocampus. Blockade of α5GABAA receptors by L-655,708 did not affect epileptiform discharges in any genotype or hippocampal segment, and the expression of α5GABAA receptors did not differ between WT and KO hippocampus. These results suggest that the increased excitability of the dorsal KO hippocampus contributes to its heightened tendency to epileptiform discharges, while the increased phasic inhibition in the Fmr1-KO ventral hippocampus may represent a homeostatic mechanism that compensates for the increased excitability reducing its vulnerability to epileptic activity.

Keywords: GABAA receptors; dorsoventral; epileptiform discharges; excitation; fragile X; hippocampus; inhibition; neurodevelopmental disorders; rat; septotemporal.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A,B) Input–output curves of fEPSP, PS, and PS/fEPSP as a function of stimulation current intensity in DH and VH of WT (A) and KO rats (B). At the bottom of graphs A and B are shown the results of statistical analysis (two-way ANOVA) of input–output curves (effect of the interaction between hippocampal segment and stimulation current intensity). Example traces of fEPSP and PS are shown in inserts; calibration bars: 1 mV, 5 ms. (C–E) Effects of genotype on fEPSP (C), PS (D), and PS/fEPSP (E) in DH (left panel) and VH (right panel). Average values of the three variables produced by stimulation current intensity of 40–70 μA are shown. Asterisks denote statistically significant difference between WT and KO (independent t-test). “ns” denotes not significant.
Figure 2
Figure 2
Paired-pulse inhibition is enhanced in VH-KO but not DH-KO. (A,B) Examples of trace recordings of the conditioning PS (PS1) and the conditioned PS (PS2) evoked by the paired-pulse stimulation in DH and VH, respectively, obtained from WT and KO rats. (C,D) Examples of input–output curves of PS1 and PS2 plotted as a function of stimulation current. Note that PS2 is suppressed more in DH-WT than in VH-WT, and that the suppression of PS2 is stronger in VH-KO than in VH-WT. (E,F) Collective data from DH and VH, respectively, showing that the average PS2/PS1 ratio is significantly lower in the VH-KO compared with VH-WT but similar in DH-WT and DH-KO. (G) Rearranged data to illustrate that the significant difference in PPI between DH-WT and VH-WT is eliminated in KO rats. Asterisks denote a statistically significant difference at p < 0.05 (independent t-test). Error bars represent SEM. “ns” denotes statistically not significant.
Figure 3
Figure 3
The protein expression of α1GABAAR is similar in DH-WT and DH-KO (A) but higher in VH-KO compared with VH-WT (B). Asterisks denote a statistically significant difference at p < 0.05 (independent t-test). “ns” denotes statistically not significant.
Figure 4
Figure 4
Comparison of Mg2+-free-induced population discharges between WT and KO. (A–D) Example trace recordings from DH (left panel) and VH (right panel) of WT and KO rats (E). Collective data are shown. Asterisks denote a statistically significant difference at p < 0.05 (independent t-test). “ns” denotes statistically not significant. Note that epileptiform discharges occur less frequently in DH-WT than VH-WT; they occur with similar frequency in DH-WT and DH-KO, but their frequency is reduced in VH-KO compared with VH-WT.
Figure 5
Figure 5
Effects of SR 95531 on epileptiform population discharges. (A–D) Example trace recordings from DH and VH of WT and KO rats, obtained under control conditions and during application of SR 95531. Calibration bars: 0.5 mV, 2 ms. (E,F) Collective data are shown for DH (E) and VH (F). Asterisks denote a statistically significant difference at p < 0.05 (independent t-test). “ns” denotes statistically not significant.
Figure 6
Figure 6
Effects of L-655,708 on epileptiform population discharges. (A–D) Example trace recordings from DH and VH of WT and KO rats, obtained under control conditions and during application of L-655,708. (E,F) Collective data are shown for DH (E) and VH (F). “ns” denotes statistically not significant. L-655,708 does not significantly affect the rate of epileptiform discharges in either segment of the hippocampus or genotype.
Figure 7
Figure 7
Protein expression of α5GABAAR in DH (A) and VH (B) from WT and KO rats. α5GABAAR displays similar expression between WT and KO hippocampus. “ns” denotes statistically not significant.
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