Inactivation of ATRX in forebrain excitatory neurons affects hippocampal synaptic plasticity

Abstract

α-Thalassemia X-linked intellectual disability (ATR-X) syndrome is a neurodevelopmental disorder caused by mutations in the ATRX gene that encodes a SNF2-type chromatinremodeling protein. The ATRX protein regulates chromatin structure and gene expression in the developing mouse brain and early inactivation leads to DNA replication stress, extensive cell death, and microcephaly. However, the outcome of Atrx loss of function postnatally in neurons is less well understood. We recently reported that conditional inactivation of Atrx in postnatal forebrain excitatory neurons (ATRX-cKO) causes deficits in long-term hippocampus-dependent spatial memory. Thus, we hypothesized that ATRX-cKO mice will display impaired hippocampal synaptic transmission and plasticity.In the present study, evoked field potentials and current source density analysis were recorded from a multichannel electrode in male, urethane-anesthetized mice. Three major excitatory synapses, the Schaffer collaterals to basal dendrites and proximal apical dendrites, and the temporoammonic path to distal apical dendrites on hippocampal CA1 pyramidal cells were assessed by their baseline synaptic transmission, including pairedpulse facilitation (PPF) at 50-ms interpulse interval, and by their long-term potentiation (LTP) induced by theta-frequency burst stimulation. Baseline single-pulse excitatory response at each synapse did not differ between ATRX-cKO and control mice, but baseline PPF was reduced at the CA1 basal dendritic synapse in ATRX-cKO mice. While basal dendritic LTP of the first-pulse excitatory response was not affected in ATRX-cKO mice, proximal and distal apical dendritic LTP were marginally and significantly reduced, respectively. These results suggest that ATRX is required in excitatory neurons of the forebrain to achieve normal hippocampal LTP and PPF at the CA1 apical and basal dendritic synapses, respectively. Such alterations in hippocampal synaptic transmission and plasticity could explain the long-term spatial memory deficits in ATRX-cKO mice and provide insight into the physiological mechanisms underlying intellectual disability in ATR-X syndrome patients.

Phasic modulation of hippocampal synaptic plasticity by theta rhythm.

“…A CSD-time contour map (Figure 3B) shows that, at a time labeled D (meaning distal), a large sink peak occurs at SLM (ch14), accompanied by major sources at RAD (ch10 -12). This CSD pattern at Time D is most similar to that associated with distal apical dendritic excitation of CA1 (Gugustea, Tamming, Martin-Kenny, Bérubé, & Leung, 2019;Leung et al, 1995;Figure 3C), in having a large SLM sink and a major RAD source. This has been called the distal dendritic excitation dipole (Leung, 1984).…”

Atrx Deletion in Neurons Leads to Sexually Dimorphic Dysregulation of miR-137 and Spatial Learning and Memory Deficits

“…The Schaffer collateral pathway involves the CA3 axons projecting to the CA1 medial apical dendrites (Vago and Kesner, 2008), whereas the temporoammonic pathway initiates in layer III of the entorhinal cortex and projects to the CA1 middle apical dendritic layer (Nguyen and Kandel, 1996). We recently reported impaired hippocampal apical dendritic CA1 long-term potentiation (LTP), which could account for the spatial memory deficits reported here (Gugustea et al, 2020). The temporoammonic pathway, thought to be critical for long-term spatial memory recall or consolidation (Brun et al, 2008;Remondes and Schuman, 2004), showed significantly reduced LTP in anesthetized Atrx-cKO Male mice compared to control mice (Gugustea et al, 2020).…”

“…We recently reported impaired hippocampal apical dendritic CA1 long-term potentiation (LTP), which could account for the spatial memory deficits reported here (Gugustea et al, 2020). The temporoammonic pathway, thought to be critical for long-term spatial memory recall or consolidation (Brun et al, 2008;Remondes and Schuman, 2004), showed significantly reduced LTP in anesthetized Atrx-cKO Male mice compared to control mice (Gugustea et al, 2020).…”

Constrained neuro fuzzy inference methodology for explainable personalised modelling with applications on gene expression data

“…Impaired oxygen transport may result in chronic low-level ischemia, to which, regions implicated in a mechanistic cascade to psychosis e.g., hippocampus 41 – 43 , are particularly vulnerable 44 . Reduced expression of ATRX is associated with hippocampal dysfunction 45 , 46 and a neurodevelopmental syndrome 47 . However, to our knowledge we are the first to associate ATRX with risk for psychosis.…”