Rescue of sharp wave-ripples and prevention of network hyperexcitability in the ventral but not the dorsal hippocampus of a rat model of fragile X syndrome

Abstract

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene (Fmr1) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABAA receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1-KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability.

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

“…Similarly, I-O curves were similar in WT and KO female DH (F9,326 = 0.034, p = 0.999; WT=15, KO=19; Figure 9C) and VH (F9,214 = 0.639, p = 0.763; WT=15, KO=8; Figure 9D). 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].…”

“…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.…”