Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models

Roy, Dheeraj S.; Zhang, Ying; Aida, Tomomi; Choi, Sung-Soon; Chen, Qian; Hou, Yuanyuan; Lea, Nicholas E.; Skaggs, Keith; Quay, Juliana; Liew, Min; Maisano, Hannah; Le, Vinh Sy; Jones, Carter; Xu, Jie; Kong, Dong; Sullivan, Heather A.; Saunders, Arpiar; McCarroll, Steven A.; Wickersham, Ian R.; Feng, Guoping

doi:10.1016/j.neuron.2021.06.005

Cited by 51 publications

(40 citation statements)

References 41 publications

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“…Furthermore, considerable Ptchd1 expression was observed in the dentate gyrus of adult (P60) mice [ 32 ]. In addition to the dentate gyrus and TRN, Ptchd1 exhibits strong expression in the anterodorsal subdivision (AD) of the thalamus in adult mice [ 13 ].…”

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

“…Murakami et al generated mice with an exon 1 deletion ( Ptchd1 Δ 1/Y ) [ 48 ], while Ko et al generated mice with an exon 3 deletion ( Ptchd1 Δ 3/Y ) [ 49 ]. Lastly, Roy et al employed Cre-dependent SpCas9 adeno-associated viruses (AAVs) to knockdown Ptchd1 ( Ptchd1 KD ) in specific brain subregions in vivo [ 13 ]. The differences in the predicted effects of these knockout strategies on Ptchd1 protein manufacture are outlined in Figure 4 .…”

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

“…Interestingly, this deficit was only present when the sample and choice trials were separated by a longer (60 s) interval, but a similar performance was observed when the inter-trial duration was short (10 s). Furthermore, these AD thalamus Ptchd1 KD mice also demonstrated impaired long-term memory recall, which was evident from a significantly reduced freezing when tested 24 h after training in a contextual fear conditioning paradigm [ 13 ]. Notably, a reduced discrimination index on the novel object recognition test (NORT) provides evidence of weakened recognition memory in both Ptchd1 Δ 1/Y and Ptchd1 Δ 2/Y mice [ 32 , 33 , 48 ].…”

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

“…Roy et al subsequently used ex vivo electrophysiology to examine neuronal properties in the Ptchd1 KD AD thalamus and identified a reduction in action potential half-width and a corresponding increase in firing frequency [ 13 ]. These authors also report that a contextual fear-conditioning paradigm did not elicit synaptic strengthening in the Ptchd1 KD AD thalamus, as evidenced by a stagnant AMPA-to-NMDA (A/N) ratio in the AD thalamus-retrosplenial cortex (RSC) circuit.…”

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

“…Since the initial discovery, almost 70 additional rare genomic variants have been identified ( Figure 1 ; Supplementary Table S1 ; , accessed on 1 August 2021). These consisted of both microdeletions, which ranged from approximately 46 Kbp to 1.2 Mbp and encompassed portions of PTCHD1 and/or PTCHD1-AS [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ], as well as single-nucleotide variants (SNVs) within the coding sequence of PTCHD1 . Of the SNVs that have been identified, 18 were inherited missense variants, four were truncating variants (one of which was de novo ), and one was an inherited nonsense mutation [ 6 , 8 , 11 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene

Pastore

Frankland

et al. 2022

Genes

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Over the last one and a half decades, copy number variation and whole-genome sequencing studies have illuminated the considerable genetic heterogeneity that underlies the etiologies of autism spectrum disorder (ASD) and intellectual disability (ID). These investigations support the idea that ASD may result from complex interactions between susceptibility-related genetic variants (single nucleotide variants or copy number variants) and the environment. This review outlines the identification and neurobiological characterization of two such genes located in Xp22.11, Patched domain-containing 1 (PTCHD1), and its antisense lncRNA PTCHD1-AS. Animal models of Ptchd1 disruption have recapitulated a subset of clinical symptoms related to ASD as well as to ID. Furthermore, these Ptchd1 mouse knockout studies implicate the expression of Ptchd1 in both the thalamic and the hippocampal brain regions as being crucial for proper neurodevelopment and cognitive function. Altered kynurenine metabolic signalling has been postulated as a disease mechanism in one of these animal studies. Additionally, ASD patient-derived induced pluripotent stem cells (iPSCs) carrying a copy number loss impacting the antisense non-coding RNA PTCHD1-AS have been used to generate 2D neuronal cultures. While copy number loss of PTCHD1-AS does not affect the transcription of PTCHD1, the neurons exhibit diminished miniature excitatory postsynaptic current frequency, supporting its role in ASD etiology. A more thorough understanding of risk factor genes, such as PTCHD1 and PTCHD1-AS, will help to clarify the intricate genetic and biological mechanisms that underlie ASD and ID, providing a foundation for meaningful therapeutic interventions to enhance the quality of life of individuals who experience these conditions.

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Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene

Pastore

Frankland

et al. 2022

Genes

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Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Xiao,

Xi,

Wang

et al. 2023

Advanced Science

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Impaired extinction of fear memory is one of the most common symptoms in post‐traumatic stress disorder (PTSD), with limited therapeutic strategies due to the poor understanding of its underlying neural substrates. In this study, functional screening is performed and identified hyperactivity in the mediodorsal thalamic nucleus (MD) during fear extinction. Furthermore, the encoding patterns of the hyperactivated MD is investigated during persistent fear responses using multiple machine learning algorithms. The anterior cingulate cortex (ACC) is also identified as a functional downstream region of the MD that mediates the extinction of fear memory. The thalamocortical circuit is comprehensively analyzed and found that the MD‐ACC parvalbumin interneurons circuit is preferentially enhanced in PTSD mice, disrupting the local excitatory and inhibitory balance. It is found that decreased phosphorylation of the Kv3.2 channel contributed to the hyperactivated MD, primarily to the malfunctioning thalamocortical circuit. Using a lipid nanoparticle‐based RNA therapy strategy, channelopathy is corrected via a methoxylated siRNA targeting the protein phosphatase 6 catalytic subunit and restored fear memory extinction in PTSD mice. These findings highlight the function of the thalamocortical circuit in PTSD‐related impaired extinction of fear memory and provide therapeutic insights into Kv3.2‐targeted RNA therapy for PTSD.

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Brain‐wide mapping of inputs to the mouse lateral posterior (LP/Pulvinar) thalamus–anterior cingulate cortex network

Leow

Zhou

Sullivan

et al. 2022

J of Comparative Neurology

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The rodent homolog of the primate pulvinar, the lateral posterior (LP) thalamus, is extensively interconnected with multiple cortical areas. While these cortical interactions can span the entire LP, subdivisions of the LP are characterized by differential connections with specific cortical regions. In particular, the medial LP has reciprocal connections with frontoparietal cortical areas, including the anterior cingulate cortex (ACC). The ACC plays an integral role in top-down sensory processing and attentional regulation, likely exerting some of these functions via the LP. However, little is known about how ACC and LP interact, and about the information potentially integrated in this reciprocal network. Here, we address this gap by employing a projectionspecific monosynaptic rabies tracing strategy to delineate brain-wide inputs to bottomup LP→ACC and top-down ACC→LP neurons. We find that LP→ACC neurons receive inputs from widespread cortical regions, including primary and higher order sensory and motor cortical areas. LP→ACC neurons also receive extensive subcortical inputs, particularly from the intermediate and deep layers of the superior colliculus (SC).Sensory inputs to ACC→LP neurons largely arise from visual cortical areas. In addition, ACC→LP neurons integrate cross-hemispheric prefrontal cortex inputs as well as inputs from higher order medial cortex. Our brain-wide anatomical mapping of inputs to the reciprocal LP-ACC pathways provides a roadmap for understanding how LP and ACC communicate different sources of information to mediate attentional control and visuomotor functions.

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Anterior thalamic dysfunction underlies cognitive deficits in a subset of neuropsychiatric disease models

Cited by 51 publications

References 41 publications

PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene

PTCHD1: Identification and Neurodevelopmental Contributions of an Autism Spectrum Disorder and Intellectual Disability Susceptibility Gene

Restoring the Function of Thalamocortical Circuit Through Correcting Thalamic Kv3.2 Channelopathy Normalizes Fear Extinction Impairments in a PTSD Mouse Model

Brain‐wide mapping of inputs to the mouse lateral posterior (LP/Pulvinar) thalamus–anterior cingulate cortex network

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