Combinatorial Targeting of Distributed Forebrain Networks Reverses Noise Hypersensitivity in a Model of Autism Spectrum Disorder

Nakajima, Miho; Schmitt, L. Ian; Feng, Guoping; Halassa, Michael M.

doi:10.1016/j.neuron.2019.09.040

Cited by 19 publications

(17 citation statements)

References 93 publications

(130 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The circuit motifs so revealed will help inform and generate computational models of the role of the cognitive thalamus, beyond that of a relay, in generating behavioral flexibility. In turn these circuit motifs may provide us with specific therapeutic targets for the treatment of cognitive deficits, as seen in neuropsychiatric disorders ( Mukherjee et al, 2019 ; Nakajima et al, 2019a ; Schmitt and Halassa, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse

Mukherjee

Bajwa

Lam

et al. 2020

eLife

View full text Add to dashboard Cite

The thalamus engages in sensation, action, and cognition, but the structure underlying these functions is poorly understood. Thalamic innervation of associative cortex targets several interneuron types, modulating dynamics and influencing plasticity. Is this structure-function relationship distinct from that of sensory thalamocortical systems? Here, we systematically compared function and structure across a sensory and an associative thalamocortical loop in the mouse. Enhancing excitability of mediodorsal thalamus, an associative structure, resulted in prefrontal activity dominated by inhibition. Equivalent enhancement of medial geniculate excitability robustly drove auditory cortical excitation. Structurally, geniculate axons innervated excitatory cortical targets in a preferential manner and with larger synaptic terminals, providing a putative explanation for functional divergence. The two thalamic circuits also had distinct input patterns, with mediodorsal thalamus receiving innervation from a diverse set of cortical areas. Altogether, our findings contribute to the emerging view of functional diversity across thalamic microcircuits and its structural basis.

show abstract

Section: Discussionmentioning

confidence: 99%

Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse

Mukherjee

Bajwa

Lam

et al. 2020

eLife

View full text Add to dashboard Cite

show abstract

“…As to the relationship between TRN and ASD, plenty of studies have been done. TRN may be involved with the hyperactivity, attention deficits, and hypersensitivity of ASD 11 – 13 . An animal model of autism, the PTCHD1 knockout mouse, was reported.…”

Section: Discussionmentioning

confidence: 99%

“…Due to its specific position and synaptic connections, TRN is thought to play an important role in sensory information processing, such as sensory detection 3 , sensory selection 4 , 5 , and sensory gating 6 , 7 . Aberrant sensory processing is common in some major psychiatry disorders, so TRN is considered as the ideal target for the investigation of the pathophysiology of schizophrenia 8 – 10 and autism spectrum disorder (ASD) 11 – 13 .…”

Section: Introductionmentioning

confidence: 99%

Involvement of the thalamic reticular nucleus in prepulse inhibition of acoustic startle

You

Luo

et al. 2021

Transl Psychiatry

View full text Add to dashboard Cite

Thalamic reticular nucleus (TRN) is a group of inhibitory neurons surrounding the thalamus. Due to its important role in sensory information processing, TRN is considered as the target nucleus for the pathophysiological investigation of schizophrenia and autism spectrum disorder (ASD). Prepulse inhibition (PPI) of acoustic startle response, a phenomenon that strong stimulus-induced startle reflex is reduced by a weaker prestimulus, is always found impaired in schizophrenia and ASD. But the role of TRN in PPI modulation remains unknown. Here, we report that parvalbumin-expressing (PV+) neurons in TRN are activated by sound stimulation of PPI paradigm. Chemogenetic inhibition of PV+ neurons in TRN impairs PPI performance. Further investigations on the mechanism suggest a model of burst-rebound burst firing in TRN-auditory thalamus (medial geniculate nucleus, MG) circuitry. The burst firing is mediated by T-type calcium channel in TRN, and rebound burst firing needs the participation of GABAB receptor in MG. Overall, these findings support the involvement of TRN in PPI modulation.

show abstract

“…These deficits presumably contribute to learning and memory impairments, as Ptchd1 Δ 2/Y mice are impaired in a cognitive task in the presence of a visual distractor, suggesting sensory-related distractibility in these mice [ 31 ]. Similarly, Ptchd1 Δ 2/Y mice demonstrated a markedly poorer ability to discriminate between different auditory stimuli when provided with high levels of background noise, both in the presence and absence of preceding visual cues [ 50 ].…”

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

“…This finding suggests a deficit of executive control over sensory filtering in Ptchd1 Δ 2/Y mice, which may be mediated by the prefrontal cortex (PFC). Remarkably, a synergistic approach that used the cognitive enhancer modafinil in combination with 1-EBIO was observed to fully restore both the PFC and the audTRN function, as well as to rescue the attenuated discrimination performance in the Ptchd1 Δ 2/Y mice when visual cues were provided [ 50 ].…”

Section: Expression Profiling Of Ptchd1 and ...mentioning

confidence: 99%

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

Pastore

Frankland

et al. 2022

Genes

View full text Add to dashboard Cite

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.

show abstract

Combinatorial Targeting of Distributed Forebrain Networks Reverses Noise Hypersensitivity in a Model of Autism Spectrum Disorder

Cited by 19 publications

References 93 publications

Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse

Variation of connectivity across exemplar sensory and associative thalamocortical loops in the mouse

Involvement of the thalamic reticular nucleus in prepulse inhibition of acoustic startle

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

Contact Info

Product

Resources

About