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

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.

Region-Related Differences in Short-Term Synaptic Plasticity and Synaptotagmin-7 in Male and Female Hippocampus of a Rat Model of Fragile X Syndrome

“…Regarding male rats, the present results conform with those of a previous study [76]. However, another study reported increased basal excitatory synaptic transmission in the DH of KO vs WT male rats [75]. This inconsistency apparently results from the different measurement approach used in the two studies to estimate excitatory synaptic transmission; in the first study the whole I-O curve as well as the average fEPSP calculated from the whole curve were compared between the two genotypes, while in the second study the average fEPSPs evoked with moderate stimulation current intensity was measured.…”

“…In contrast to male rats, we found increased excitatory synaptic transmission in the DH compared with VH of WT female rats (F9,289 = 2.837, p = 0.003; DH=15, VH=15; Figure 9C) but not KO female rats (F9,251 = 0.376, p = 0.946; DH=19, VH=8; Figure 9D). The results regarding male WT rats confirm previously reported observations [63,75,[83][84][85]. Regarding female rats, to the best of our knowledge this is the first time that basal excitatory synaptic transmission is compared between DH and VH in female rats.…”

“…For instance, seizures that are a common trait of FXS young individuals [2,91], often involving the anterior hippocampus (that corresponds to the ventral hippocampus in rodents), are absent in adults [2,91,92]. Moreover, the recently shown increase of GABAergic inhibition specifically in the ventral hippocampus of adult KO rats [75,76], the brain region most susceptible to epilepsy [93,94], may represent the result of homeostatic mechanisms activated during the development of individuals with the FXS, in an attempt to compensate for the increased excitability of the brain. Thus, it is tempting to speculate that the normal STSP we found in adult male KO rats may represent the result of adaptive mechanisms that attempt to restore the disrupted STSP in immature KO animals [17,19,21,60].…”

“…Dorsal and ventral hippocampus express remarkably different patterns of STSP [61][62][63][64][65][66][67][68][69][70][71][72][73], and they are involved in different ways with brain functions such as cognition and emotion [74]. Interestingly, the dorsal and ventral hippocampus have been recently shown to respond differently to FXS with respect to network excitability, GABAergic inhibition, and rhythmogenesis [75,76]. It is therefore necessary to study possible effects of FXS on STSP separately in the two segments of the hippocampus.…”