Introduction: Fragile X messenger ribonucleoprotein (FMRP) is a protein involved in many neuronal processes in the nervous system including the modulation of synaptic transmission. The loss of FMRP produces the fragile X syndrome (FXS), a neurodevelopmental disorder affecting synaptic and neuronal function and producing cognitive impairments. However, the effects of FXS on short-term processing of synaptic inputs and neuronal outputs in the hippocampus have not yet been sufficiently clarified. Furthermore, it is not known whether dorsal and ventral hippocampi are affected similarly or not in FXS. Method: We used an Fmr1 knockout (KO) rat model of FXS and recordings of evoked field potentials from the CA1 field of transverse slices from both the dorsal and the ventral hippocampi of adult rats. Results: Following application of a frequency stimulation protocol consisting of a ten-pulse train and recordings of fEPSP, we found that the dorsal but not ventral KO hippocampus shows altered short-term synaptic plasticity. Furthermore, applying the frequency stimulation protocol and recordings of population spikes, both segments of the KO hippocampus display altered short-term neuronal dynamics. Conclusions: These data suggest that short-term processing of synaptic inputs is affected in the dorsal, not ventral, FXS hippocampus, while short-term processing of neuronal output is affected in both segments of the FXS hippocampus in a similar way. These FXS-associated changes may have significant impact on the functions of the dorsal and ventral hippocampi in individuals with FXS.

Fragile X messenger ribonucleoprotein (FMRP) or fragile X protein [1], previously called fragile X mental retardation protein, is a widely expressed protein in the nervous system encoded by the Fmr1 gene on the X chromosome [2, 3]. FMRP is involved in many functions in the brain by binding to mRNAs and regulating the translation process, as well as by directly modulating other proteins [4‒7]. Many processes regulated by FMRP are related to the development and function of synapses. Notably, FMRP regulates mRNAs and proteins that are involved in synaptogenesis, expression and function of ion channels and neurotransmitter receptors, synaptic structure, and synaptic plasticity [2, 6, 8‒18]. For instance, Deng et al. [14] have shown that the loss of FMRP leads to enhanced frequency facilitation in the middle hippocampus of immature mice, and this fragile X syndrome (FXS)-associated alteration was attributed to increased augmentation and reduced short-term depression, which represent additional forms of short-term synaptic plasticity (STSP).

Mutation in the promoter region of the Fmr1 gene causes the suppression or loss of FMRP production [2, 19‒21], resulting in the so-called FXS, a developmental disorder characterized by hyperactivity, sensory hypersensitivity, deficits in learning and memory processes, social deficits, and vulnerability to epileptic activity [5, 22]. FXS represents the most common cause of inheritable intellectual disability and a common genetic cause of autism spectrum disorder [23‒25]. To study the neurobiological correlates of FXS, several animal models characterized by the loss of FMRP have been developed. Fmr1 knockout (KO) animals display several abnormalities at the neuronal and behavioral level, including altered neural circuit excitability, cognitive impairments, hyperexcitability, and disturbed information processing [7, 24‒27].

A plethora of changes have been detected in the FXS hippocampus including altered neuronal excitability [28‒33], altered network oscillations [34], increased susceptibility to epileptiform discharges [11], altered GABA signaling [10, 35‒38], and dysregulated long-term synaptic plasticity [12, 39, 40]. However, a consensus about the impact of these changes on the hippocampus-dependent functions is missing, presumably because the hippocampus is a functionally heterogeneous brain structure, and neurophysiological examinations of FXS effects have been performed exclusively in the dorsal segment of the hippocampus. However, the dorsal and the ventral segments of the hippocampus are unequally involved in developmental and neuropsychiatric disorders including depression [41‒43] and schizophrenia [44]. In particular, the close association of the ventral hippocampus with social cognition [45‒49] and anxiety [50‒53], functions that are affected in various neurodevelopmental disorders [7, 54], make the ventral hippocampus a brain structure with key involvement in neurodevelopmental disorders. Accordingly, several aspects in the functional organization of the ventral hippocampus have been found altered or disrupted in animal models of neurodevelopmental disorders, such as autism spectrum disorders (ASDs). For instance, the proportion of the ventral hippocampus CA1 social memory neurons is reduced in the ShanK3 KO mice [47], while activation of the pathway from CA2 to the ventral CA1 hippocampal neurons rescues social memory deficits in both the ShanK3 KO [55] and Mecp2 KO mice [48], which are animal models of Rett syndrome. The ventral hippocampus input to prefrontal GABAergic cells is disrupted in the Pogz mutant mice, an animal model of ASD, which displays reduced anxiety-related avoidance behavior [56], as well as the number of adult-born neurons is reduced in the ventral dentate gyrus of Neuroligin3 knockin mouse model of ASD [57].

However, little is known about the effects of FXS on the neurophysiology of dorsal and ventral hippocampi. For instance, the ventral dentate gyrus shows reduced number of surviving cells in Fmr1 KO mice model of FXS [51], and long-term voluntary running enhances cell survival in the dorsal but not ventral dentate gyrus in the same mouse model [58], while substantial decrease in the number of immature neurons has been found in the ventral hippocampus of Cntnap2−/− and Shank3+/ΔC mice [59]. Apparently, however, the ventral hippocampus exhibits considerable plasticity in compensating for certain developmental disturbances. It has been recently shown that the ventral hippocampus of adult Fmr1 KO rats displays increased effectiveness of GABAergic inhibition, increased expression of GABAA receptors, and reduced susceptibility to epileptiform activity [60, 61]. Also, the proportion of surviving cells that become neurons is increased in the shrinking population of these cells in the dentate gyrus of Fmr1 KO ventral hippocampus [51]. Accordingly, it can be suggested that these changes may represent attempts to homeostatically maintain normal function as, for instance, is evidenced by the unaltered activity of sharp wave-ripples found in the ventral FXS hippocampus [60]. It is therefore important to investigate whether basic physiological phenomena such as short-term changes in synaptic and neuronal activity are affected by FXS in the dorsal and ventral hippocampi.

FXS impacts on information processing in the brain and provokes alterations in behavior [22, 30, 62, 63] that are presumably associated with short-term forms of synaptic plasticity and short-term dynamics of neuronal firing. Activity-dependent short-term and long-term changes in synaptic transmission and neuronal firing represent fundamental functional aspects in brain circuits involved in several functions including temporal filtering, dynamic gain control, stabilization of network activity, synaptic input diversification, processing of ongoing activity, and activity propagation between brain regions [64‒73]. Therefore, changes in the patterns of synaptic transmission and neuronal firing during rapidly repetitive activity and the resultant altered communication between neuronal populations may underlie aberrant behavioral phenotypes [74‒76]. Considering that FMRP has a deep involvement in regulating synaptic function [2, 6, 8‒18], we hypothesized that its deficiency in FXS may negatively affect short-term changes in synaptic plasticity. Furthermore, considering that phenomena of STSP are unevenly expressed along the long axis of the hippocampus [77‒84], we wondered whether the FXS-associated loss of FMRP affects differently the two opposite segments of the hippocampus.

Despite the large body of evidence about the effects of FXS on long-term synaptic plasticity [12, 13, 85‒87], evaluation of STSP in FXS models is still limited. In this study, we choose to examine phenomena of STSP comparatively between the dorsal and ventral hippocampi in an Fmr1 KO rat model of FXS. In addition, we studied the properties of short-term dynamics of neuronal output (short-term neuronal dynamics, STND) since the neuronal output represents the integration of synaptic and neuronal computations and determines the functional role that a local neuronal network plays in the framework of a brain function. Notably, to the best of our knowledge, possible defects in short-term dynamics of neuronal firing in FXS have not been examined before.

Animals and Preparation of Hippocampal Slices

Long Evans (LE) male rats were used in this study. Both WT and Fmr1 KO LE rats were purchased from Medical College of Wisconsin (RRIDs: RGD_2308852 and RGD_11553873, respectively). Rats were maintained under stable conditions of light-dark cycle (12/12 h), temperature (20–22°C), and they had free access to food and water, at the specific pathogen-free Laboratory of Experimental Animals of the Department of Medicine of the University of Patras (license No.: EL-13-BIOexp-04). The treatment of animals and all experimental procedures used in this study were conducted in accordance with the European Communities Council Directive Guidelines for the Care and Use of Laboratory Animals (2010/63/EU – European Commission) and approved by the Protocol Evaluation Committee of the Department of Medicine of the University of Patras and the Directorate of Veterinary Services of the Achaia Prefecture of Western Greece region (reg. number: 5661/37, January 18, 2021). This experimental study has also been reviewed and approved by Research Ethics Committee of the University of Patras. Rats were genotyped using tail or brain tissue to test the expression of FMRP by means of Western blotting as described below.

We prepared slices from both the dorsal and the ventral hippocampi of WT and KO rats. Specifically, we decapitated each individual rat under conditions of deep anesthesia with diethyl-ether; then, the brain was removed from the cranium and placed in ice-cold (2–4°C) standard artificial cerebrospinal fluid containing, in mm: 124 NaCl, 4 KCl, 2 CaCl2, 2 MgSO4, 26 NaHCO3, 1.25 NaH2PO4, and 10 glucose. The medium was equilibrated with a gas mixture containing 95% O2 and 5% CO2 at a pH = 7.4. The two hippocampi were removed from the brain and positioned on a McIlwain tissue chopper where 500 μm thick slices were prepared from the two segments of the hippocampus, extending between 0.5 mm and 3.5 mm from each end of the structure, by cutting the hippocampus transversely to its long axis (Fig. 1a). Immediately after their preparation, slices were transferred to an interface type recording chamber where they were maintained at a constant temperature of 30 ± 0.5°C and were constantly perfused with artificial cerebrospinal fluid of the same composition as described above, at a perfusion rate of ∼1.5 mL/min and humidified with a mixed gas consisting of 95% O2 and 5% CO2. The slices were left for at least one and a half hours to recover, and then stimulation and recording were started.

Fig. 1.

Illustration of short-term phenomena measured in this study. a Examples of paired synaptic responses (fEPSP) and paired-pulse ratio (PPR) evoked at two different inter-pulse intervals, 50 ms and 200 ms. Traces were obtained from two dorsal hippocampal slices. b Frequency facilitation (FF) and frequency depression (FD) of fEPSP (upper and lower trace, respectively). Note that the steady-state response (i.e., the average of 8th–10th responses, dotted line box) is increased in FF and decreased in FD. Dotted line indicates the response of the conditioning fEPSP (i.e., the first fEPSP in a train). c Examples of neuronal output (PS) evoked by the frequency stimulation protocol at 30 Hz (upper trace) and 40 Hz (lower traces). Dotted line boxes indicate the onset and steady-state responses. In the example of frequency facilitation both onset and steady-state response are facilitated with respect to the conditioning response, while in the example of frequency depression, both responses are depressed. It is noted that depending on the stimulation frequency and the experimental condition used, an increase in the onset response may be accompanied by a depression of the steady-state response, and vice versa. Upper traces (b, c) were obtained from the dorsal hippocampal slices, while lower traces were obtained from the ventral hippocampal slices.

Fig. 1.

Illustration of short-term phenomena measured in this study. a Examples of paired synaptic responses (fEPSP) and paired-pulse ratio (PPR) evoked at two different inter-pulse intervals, 50 ms and 200 ms. Traces were obtained from two dorsal hippocampal slices. b Frequency facilitation (FF) and frequency depression (FD) of fEPSP (upper and lower trace, respectively). Note that the steady-state response (i.e., the average of 8th–10th responses, dotted line box) is increased in FF and decreased in FD. Dotted line indicates the response of the conditioning fEPSP (i.e., the first fEPSP in a train). c Examples of neuronal output (PS) evoked by the frequency stimulation protocol at 30 Hz (upper trace) and 40 Hz (lower traces). Dotted line boxes indicate the onset and steady-state responses. In the example of frequency facilitation both onset and steady-state response are facilitated with respect to the conditioning response, while in the example of frequency depression, both responses are depressed. It is noted that depending on the stimulation frequency and the experimental condition used, an increase in the onset response may be accompanied by a depression of the steady-state response, and vice versa. Upper traces (b, c) were obtained from the dorsal hippocampal slices, while lower traces were obtained from the ventral hippocampal slices.

Close modal

Electrophysiological Recordings and Data Analysis

Recordings of evoked field potentials were made from the stratum radiatum and stratum pyramidale of the CA1 hippocampal region, following electrical stimulation of Schaffer collaterals and consisted of field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs), respectively. Electrical stimulation consisted of constant current pulses with a stable duration of 100 μs and variable amplitude (20–300 μA). Stimulation current was delivered using a home-made bipolar platinum/iridium wire electrode with a wire diameter of 25 μm and an interwire distance of 100 μm; wire was purchased from World Precision Instruments, USA. Recordings were made using a 7 μm-thick carbon fiber electrode (Kation Scientific, Minneapolis, USA). Stimulation and recording electrodes were placed 300–400 μm apart. Baseline stimulation was delivered every 30 s using a stimulation current intensity that elicited a fEPSP with a slope of about 1 mV/ms and/or a PS of amplitude of about 1 mV. fEPSP was quantified by the maximum slope of the early rising phase; PS was quantified by its amplitude measured as the length of the projection of the minimum peak on the line connecting the two maxima peaks of the PS waveform. Short-term changes in synaptic transmission and neuronal excitation were studied using a frequency stimulation protocol as previously described [79, 88]. Specifically, the frequency stimulation protocol consisted of a sequence of ten consecutive pulses delivered at varying frequency between 0.1 and 100 Hz, resembling the short bursts that are typical in hippocampal pyramidal cells [89]. In each experiment, stimulation trains of different frequency were applied randomly. Stimulation trains were separated by 2-min-long intervals. The effect of frequency stimulation on fEPSP or PS was quantified as the percentage change of each of the nine conditioned responses with respect to the conditioning (first) response in a train. Using this protocol, we studied two phenomena of STSP and two phenomena of STND. Notably, regarding synaptic transmission, we studied: a) the paired-pulse ratio (PPR), i.e., the ratio between the first conditioned response (fEPSP2) and the conditioning response (fEPSP2/fEPSP1), and b) the average rate of change of the last three conditioned responses (8th–10th) with respect to the conditioning response. Regarding the functional output of the network (expressed by PS), we studied (a) the onset response, i.e., the first conditioned PS with respect to the conditioning PS, and (b) the average rate of change of the last three conditioned responses (8th–10th) with respect to the conditioning response. In either case, the average of the last three conditioned responses (8th–10th) is named the steady state response. An increase in steady state response is described as frequency facilitation (FF), and a decrease in steady state response is described as frequency depression (FD). Figure 1 illustrates examples of PPR and FF/D in STSP, and the onset response and FF/D in STND.

Signal was acquired and amplified X500 and then filtered at 0.5 Hz–2 kHz using Neurolog amplifiers (Digitimer Limited, UK); signal was digitized at 10 kHz and stored on a computer disk for off-line analysis using the CED 1401-plus interface and the Spike software, respectively (Cambridge Electronic Design, Cambridge, UK).

FMRP Detection

Following the excision of the hippocampus, parts of the remaining brain tissue were stored at −80°C for a post-mortem protein expression analysis. Later, 20–40 mg tissue samples from various rats were solubilized in 200–400 μL of lysis buffer containing 1% SDS and protease inhibitors at a 1:100 dilution and homogenized with sonication. Alternatively, the tip of the tail of a living rat was solubilized in 200 μL of lysis buffer and homogenized, as described previously, in the case of ante-mortem protein expression analysis. The protein concentration for each brain or tail extract was determined by using the NanoDrop 2000 spectrophotometer (Thermo Scientific, Waltham, MA, USA). A 40–50 μg electrophoresis sample was generated from each protein sample by adding ×5 sample buffer to the appropriate protein sample volume, followed by 5 min boiling. Proteins were separated by SDS polyacrylamide gel electrophoresis and transferred to a polyvinylidene difluoride membrane (Amersham Hybond-P Western blotting PVDF membrane, Sigma, GE10600029) by Western blotting. After 1 h of blocking at room temperature in a phosphate-buffered saline containing 0.1% Tween 20 (PBS-Tween 20) and 5% nonfat dried milk, the PVDF membrane was incubated at 4°C overnight with a rabbit anti-FMRP polyclonal antibody (1:1,500 dilution, Abcam, 17722). The blot was rinsed 3 times for 5 min with PBS-Tween 20 and then incubated with goat anti-rabbit horseradish peroxidase-linked secondary antibody (1:3,000 dilution, Cell Signaling, #7074) for 1 h at room temperature. Both antibodies were diluted in PBS-Tween 20 buffer containing 3% nonfat dried milk. Immunodetection was carried out using an enhanced chemiluminescence detection system (Pierce ECL Western Blotting Substrate, Thermo Scientific, 32209) as per the manufacturer’s instructions. Chemiluminescence from the blots was detected by exposing the membranes to X-ray film (Super RX-N, Fujifilm, 47410-19289) for 20 s to 5 min, and FMRP expression was confirmed by the detection of a protein band at 75–80 kDa.

Statistics

The univariate full factorial (UNIANOVA) general linear model with fixed-effect factors was used to access the effects of the genotype or hippocampal segment. The statistics were performed using the number of slices. Throughout the text, the number of slices and animals used in each condition and parameter is given as a ratio: slices/rats. We tried to keep a reduced ratio slices/rats, close to unit.

STSP and STND Differ between the Dorsal and Ventral WT Hippocampi

We compared STSP and STND between the dorsal and ventral hippocampi of WT rats. As previously reported [79, 88], we observed large dorso-ventral differences in both phenomena. Specifically, comparing the first conditioned response which expresses the PPR, we found that dorsal and ventral WT hippocampi differ across almost all stimulation frequencies (UNIANOVA, F1,467 = 389.6, p < 0.001; Fig. 2a, PPR). Similarly, steady-state response significantly differs between the two segments of the hippocampus (UNIANOVA, F1,467 = 324.6, p < 0.001; Fig. 2b, FF/D steady state). STND also greatly differs between the dorsal and ventral WT hippocampus in terms of the first conditioned response (UNIANOVA, F1,555 = 23.15, p < 0.001; Fig. 2c, onset response) and steady-state response (UNIANOVA, F1,553 = 103.38, p < 0.001; Fig. 2d, FF/D steady state).

Fig. 2.

STSP (a-b) and STND (c–d) differ between dorsal and ventral WT hippocampi. Data for the first conditioning response that measures PPR (a) and onset response (c), and the steady-state response (FF/D steady state, b, d), are shown. The number of slices/rats used is indicated in parenthesis.

Fig. 2.

STSP (a-b) and STND (c–d) differ between dorsal and ventral WT hippocampi. Data for the first conditioning response that measures PPR (a) and onset response (c), and the steady-state response (FF/D steady state, b, d), are shown. The number of slices/rats used is indicated in parenthesis.

Close modal

FXS Affects STSP in the Dorsal but Not Ventral Hippocampi

Then, we proceeded to examine the properties of STSP in the dorsal and ventral hippocampi of WT and KO rats using a frequency stimulation paradigm. Considering that the magnitude of the first response (fEPSP) greatly determines the properties of short-term changes in synaptic transmission during stimulation trains of variable frequency [88, 90], we applied frequency stimulation starting with a conditioning fEPSP of 0.5–1.0 mV/ms. In particular, the first fEPSP (fEPSP1) in each train delivered in dorsal hippocampal slices was similar in WT (0.83 ± 0.03 mV/ms, n = 23/14) and KO group (0.82 ± 0.04 mV/ms, n = 11/7). Similarly, the first fEPSP in each train delivered in ventral hippocampal slices was similar in WT (0.83 ± 0.03 mV/ms, n = 22/13) and KO (0.82 ± 0.08 mV/ms, n = 14/10) groups.

Under these conditions we found that genotype did not significantly affect PPR (the first conditioned response) either in the dorsal (UNIANOVA, F1,385 = 0.376, p = 0.54; Fig. 3a) or the ventral hippocampi (UNIANOVA, F1,356 = 0.176, p = 0.675; Fig. 3d). However, we found a significant effect of genotype on STSP in the dorsal hippocampus when either the average of all conditioned responses (responses 2–10) were considered (UNIANOVA, F1,385 = 5.05, p = 0.025; Fig. 3c, FF/D All Conditioned fEPSPs) or when only the steady-state responses were considered (responses 8–10; UNIANOVA, F1,385 = 6.06, p = 0.014; Fig. 3b, FF/D steady state). In contrast, STSP in the ventral hippocampus did not significantly differ between the two genotypes as observed for steady-state responses (UNIANOVA, F1,356 = 0.473, p = 0.492; Fig. 3e, FF/D steady state) or the average of all conditioned responses (UNIANOVA, F1,356 = 0.028, p = 0.867; Fig. 3f, FF/D All Conditioned fEPSPs). These results suggested that FXS affects STSP in the dorsal hippocampus only.

Fig. 3.

Genotype affects STSP in the dorsal (a–c) but not ventral hippocampi (d–f). Example traces are shown on top of graphs (stimulation artifacts are truncated). Calibration bars in examples with stimulation frequency: 25 ms, 1 mV. The results of UNIANOVA are shown on the bottom of each graph.

Fig. 3.

Genotype affects STSP in the dorsal (a–c) but not ventral hippocampi (d–f). Example traces are shown on top of graphs (stimulation artifacts are truncated). Calibration bars in examples with stimulation frequency: 25 ms, 1 mV. The results of UNIANOVA are shown on the bottom of each graph.

Close modal

Similar Effects of FXS on STND in the Dorsal and Ventral Hippocampi

In addition to STSP, dynamic fluctuations of neuronal excitability greatly contribute to determining how information is transmitted in brain circuits [91‒94]. Therefore, we proceeded to examine the properties of STND in the dorsal and ventral hippocampi of WT and KO rats. Like STSP, the effect of frequency stimulation on STND strongly depends upon initial conditions, i.e., the magnitude of the first conditioning response (PS1) [88]. Accordingly, we applied frequency stimulation starting with a conditioning PS of about 1.5 mV. In particular, the first PS (PS1) in each train delivered in dorsal hippocampal slices was 1.41 ± 0.03 mV (n = 42/25) in WT and 1.4 ± 0.02 mV (n = 47/28) in KO rats; similarly, the conditioning PS in each train delivered in ventral hippocampal slices was 1.1 ± 0.04 mV (n = 34/20) in WT and 1.1 ± 0.05 mV (n = 44/28) in KO rats.

Under these conditions, we found that the genotype produced a significant effect on the onset response, i.e., the first conditioned response in a train, in both the dorsal (UNIANOVA, F1,961 = 12.71, p < 0.001; Fig. 4a onset response) and the ventral hippocampi (UNIANOVA, F1,571 = 11.44, p = 0.001; Fig. 4d, onset response). However, we found no genotype-related significant effects on STND in the dorsal hippocampus when the average of all conditioned responses (responses 2–10; UNIANOVA, F1,900 = 0.000, p = 0.989; Fig. 4c, FF/D all responses) or the steady-state responses were considered (responses 8–10; UNIANOVA, F1,961 = 0.223, p = 0.637; Fig. 4b, FF/D steady state). Similarly, we found no significant genotype-dependent effect on STND in the ventral hippocampus when either all conditioned responses (responses 2–10) were considered together (UNIANOVA, F1,497 = 1.46, p = 0.227; Fig. 4f, FF/D all responses) or when the steady-state responses were considered (responses 8–10; UNIANOVA, F1,570 = 0.076, p = 0.783; Fig. 4e, FF/D steady state). These results suggested that FXS affects the onset response during repetitive activation in the two segments of the hippocampus similarly, in the case of STND.

Fig. 4.

Genotype affects STND in the dorsal (a-c) and ventral hippocampi (d–f). Example traces are shown on top of graphs (stimulation artifacts are truncated). The results of UNIANOVA are shown at the bottom of each graph. Calibration bars in examples with stimulation frequency, 25 ms, 1 mV.

Fig. 4.

Genotype affects STND in the dorsal (a-c) and ventral hippocampi (d–f). Example traces are shown on top of graphs (stimulation artifacts are truncated). The results of UNIANOVA are shown at the bottom of each graph. Calibration bars in examples with stimulation frequency, 25 ms, 1 mV.

Close modal

In this study, we compared STSP and STND between WT and KO hippocampus. We found that STSP is altered in the dorsal but not ventral hippocampus of KO versus WT rats, while STND is altered similarly in the two hippocampal segments of KO rats. These are the first comparative data of STSP and STND along the hippocampus in an animal model of FXS.

We found that PPR, a simple form of STSP, remains normal in the KO hippocampus. Generally, these results are in keeping with previous studies [9, 12, 14]. Unlike PPR, FF/D, which is another form of STSP, significantly differs between WT and KO hippocampi. Furthermore, the alteration in FF/D was detected in the dorsal but not the ventral hippocampi. These alterations in STSP seen in KO are consistent with the changes in synaptic proteome and the morphological abnormalities observed after the loss of FMRP [14, 15], and suggest that the loss of FMRP leads to significant reduction in frequency facilitation displayed by excitatory hippocampal synapses during brief bursts of presynaptic activation.

It is interesting, however, that the reduction in frequency facilitation in the dorsal hippocampus found in the present study is contrary to the enhancement of augmentation found previously in a mouse model of FXS [14]. This discrepancy may result from the different segments of the hippocampus used in the two studies, and that single cell responses were recorded in the study by Den et al. [95] while population responses were recorded here. An alternative explanation could be related to the different rodent species used; in the present study, we used rats instead of mice in the previous one. However, a more plausible cause of this discrepancy may be related to the age of experimental animals used. In all previous studies examining hippocampal STSP, prepubertal animals were used, i.e., younger than 50 days of age, when rats reach sexual maturity [95]. Furthermore, hippocampus-dependent learning and place cell properties start between the second and third postnatal week, but most of them do not reach maturity before 5 weeks of age [96]. Importantly, synaptic facilitation at CA3-CA1 hippocampal synapses is reduced between the second and fifth week after birth in rats [97‒99]. Interestingly, FXS is characterized by a conspicuous reduction in the susceptibility to epilepsy between childhood and adulthood [100, 101], suggesting that neural networks can undergo significant reorganization in the developing FXS brain. Accordingly, it is important to consider the age of the animals in studies of synaptic plasticity, especially when these studies concern neurodevelopmental disorders such as FXS.

The output of a brain region affects the function of its target regions. In this regard, the change in STND in both dorsal and ventral FXS hippocampi would be expected to affect the activity of those brain regions to which the two hippocampal divisions send their output. However, the effects may not be the same for the two segments because the ventral hippocampus has a particularly more heterogeneous set of target regions compared with the dorsal hippocampus with ventral CA1 neurons projecting to multiple targets [102]. For instance, the ventral hippocampus, through its connections with multiple brain regions including lateral hypothalamus, medial prefrontal cortex, nucleus accumbens, and basolateral amygdala [103, 104], plays important roles in several behaviors including stress response, anxiety, fear, and social function; reviewed by [105‒107], which are altered in FXS [7]. Accordingly, disruption of neural activity in the ventral hippocampus may have more pronounced FXS-associated behavioral effects compared with the dorsal hippocampus.

In conclusion, we demonstrate that the deficiency of FMRP leads to a reduced frequency facilitation of synaptic response in the dorsal KO hippocampus and a reduced frequency facilitation and enhanced frequency depression of the neuronal output in both segments of KO hippocampus, suggesting that I-O function and the properties of information processing are altered in the FXS hippocampus. More specifically, the present data suggest that the facilitation of synaptic inputs is limited in the FXS dorsal hippocampus and the CA1 output is depressed more in KO than WT hippocampus. Furthermore, these results suggest that FXS-associated differences exist not only between different brain regions but even inside a brain structure and provide a basis for further investigation of the impact of FXS on hippocampus-dependent functions.

This study protocol was reviewed and approved by the Research Ethics Committee of the University of Patras, and the Directorate of Veterinary Services of the Achaia Prefecture of Western Greece Region (reg. number: 5661/37, January 18, 2021). The treatment of animals and all experimental procedures used in this study were conducted in accordance with the European Communities Council Directive Guidelines for the Care and Use of Laboratory Animals (2010/63/EU – European Commission).

The authors have no conflicts of interest to declare.

This research has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship, and Innovation, under the call RESEARCH – CREATE – INNOVATE (project code: T2EDK – 02075). G. Tsotsokou was financially supported by the «Andreas Mentzelopoulos » Foundation as a recipient of a Ph.D. fellowship. The publication of the article in OA mode was financially supported by HEAL-Link.

L.J.L., P.F., G.Tr., G.Ts., A.M., and E.K.: data acquisition and analysis, contribution to final text editing. P.R.: contribution to experiments’ supervision and project administration. C.P.: conception, design, and supervision of the research, data analysis, project administration, preparation, and writing the manuscript. All authors have read and approved the manuscript.

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon reasonable request.

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