Kizimenko, A. | bioRxiv Science

bioRxiv2025

Fmr1 KO causes delayed rebound spike timing in mediodorsal thalamocortical neurons through regulation of HCN channel activity

BackgroundThe neurodevelopmental disorder Fragile X syndrome (FXS) results from hypermethylation of the FMR1 gene which prevents FMRP production. FMRP modulates the expression and function of a wide variety of proteins, including voltage-gated ion channels such as Hyperpolarization-Activated Cyclic Nucleotide gated (HCN) channels, which are integral to rhythmic activity in thalamic structures. Thalamocortical pathology, particularly involving the mediodorsal thalamus (MD), has been implicated in neurodevelopmental disorders. MD connectivity with mPFC is integral to executive functions like working memory and social behaviors that are disrupted in FXS. MethodsWe used a combination of retrograde labeling and ex vivo brain slice whole cell electrophysiology in 40 wild type and 42 Fmr1 KO male mice to investigate how a lack of Fmr1 affects intrinsic cellular properties in lateral (MD-L) and medial (MD-M) MD neurons that project to the medial prefrontal cortex (MD[->]mPFC neurons). ResultsIn MD-L neurons, Fmr1 knockout caused a decrease in HCN-mediated membrane properties such as voltage sag and membrane afterhyperpolarization. These changes in subthreshold properties were accompanied by changes in suprathreshold neuron properties such as the variability of action potential burst timing. ConclusionsIn Fmr1 knockout mice, reduced HCN channel activity in MD[->]mPFC neurons impairs both the timing and magnitude of HCN-mediated membrane potential regulation. Changes in response timing may adversely affect rhythm propagation in Fmr1 KO thalamocortical circuitry. MD thalamic neurons are critical for maintaining rhythmic activity involved in cognitive and affective functions. Understanding specific mechanisms of thalamocortical circuit activity may lead to therapeutic interventions for individuals with FXS.

neuroscience↗

bioRxiv2021

Two contrasting mediodorsal thalamic circuits target the medial prefrontal cortex

At the heart of the prefrontal executive and limbic networks is the mediodorsal thalamus (MD). Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, virtually nothing is known about the physiology of neurons in MD. Here, we injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult (8 - 12 week old) male and female wildtype mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD[->]mPFC neurons). MD[->]mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. We found that that MD-M[->]mPFC neurons have longer membrane time constants, higher membrane resistance, less Hyperpolarization and Cyclic Nucleotide gated (HCN) channel activity, and more readily generate action potentials compared to MD-L[->]mPFC neurons. Additionally, MD-M[->]mPFC neurons have larger and more complex dendritic arbors compared to MD-L[->]mPFC neurons. These data demonstrating that the two populations of MD[->]mPFC neurons have distinct physiologies and morphologies suggests a differential role in thalamocortical information processing and potentially behavior.

neuroscience↗