Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

Abstract

Background Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1−/y). Methods We recorded from the CA1 in Fmr1−/y and WT littermates over six 10-min exploration sessions in a novel environment—three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1−/y rats, respectively. Results On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1−/y rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1−/y rats. These findings were consistent with increased excitability of Fmr1−/y CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1−/y rats. Limitations It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1−/y rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. Conclusions In conclusion, we found that hippocampal place cells from Fmr1−/y rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS.

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

“…A main neurophysiological correlate of FXS is an alteration of E-I balance towards excitation [11,12]. In keeping with previous observations [88][89][90][91][92][93][94], we report that loss of FMRP is accompanied by increased excitability of the hippocampal network. Additionally, it is widely thought that a crucial determining factor in the FXS-associated increase of the E-I ratio is the reduction in inhibition [95,96].…”

From synapses to circuits: What mouse models have taught us about how autism spectrum disorder impacts hippocampal function

“…Lu et al (Lu et al, 2016) used both 2-photon calcium imaging and in vivo electrophysiology to establish that while CA1 pyramidal cells in the KO mice are overall less active, they showed a significant increase in synchronous activity, which interestingly could be rescued by deep brain stimulation of the fornix. A second study employing high-density tetrode recording in the CA1 region (Kee et al, 2018) found that, like what was reported in the Fmr1-KO rats (Asiminas et al, 2022), place fields in the KO mice failed to show experience-dependent improvements in the spatial coding. Interestingly, the authors also observed the hypersynchronous activity in these mice extended to the SWR events, perhaps occluding learning-dependent consolidation mechanisms necessary for place field refinement.…”

“…More recently (Asiminas et al, 2022) Asiminas et al reported the first in vivo recordings from the hippocampus of a rat model of FXS. They observed while place fields in a novel environment were similar between control and Fmr1-KO rats, the FXS-model animals failed to show experience-dependent improvements in spatial coding when returned to the context the following day.…”

Current Best Practices for Analysis of Dendritic Spine Morphology and Number in Neurodevelopmental Disorder Research

“…This approach has a significant benefit in that you can measure both functional and structural correlates of spine density in the same cells from the same animal. Combining these recordings with pharmacological blockage of voltage-gated sodium channels using tetrodotoxin allows for determination of the quantal synaptic properties of a given neuron . These can then be combined with methods, such as two-photon glutamate uncaging, to measure the activity of individual identified dendritic spines, and super-resolution imaging .…”

“…Combining these recordings with pharmacological blockage of voltage-gated sodium channels using tetrodotoxin allows for determination of the quantal synaptic properties of a given neuron. 100 These can then be combined with methods, such as two-photon glutamate uncaging, to measure the activity of individual identified dendritic spines, and super-resolution imaging. 55 While this latter study may be the extreme end of functional analysis, further studies have shown the importance of correlating spine structure and function.…”