Cortical wiring by synapse type–specific control of local protein synthesis

Bernard, C.; Exposito-Alonso, David; Selten, Martijn; Sanalidou, Stella; Hanusz-Godoy, Alicia; Aguilera, Alfonso; Hamid, Fursham; Oozeer, Fazal; Maeso, Patricia; Allison, Leanne; Russell, Mark; Fleck, Roland A.; Rico, Beatriz; Marı́n, Oscar

doi:10.1126/science.abm7466

Cited by 34 publications

(20 citation statements)

References 75 publications

(71 reference statements)

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“…To our knowledge, this is the first demonstrated genetic rescue of congenital hydrocephalus. This data is consistent with previous findings showing that mTOR deletion leads to reduced MGE size 79 , and that mTOR activation causes selectively increased connectivity and excitatory input to parvalbumin+ interneurons 185 . We also showed that early post-natal pharmacological inhibition of mTOR increased survival, reduced ventriculomegaly, and prevented interneuron pathology in Pten cKO mice.…”

Section: Discussionsupporting

confidence: 93%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

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Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders.

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Section: Discussionsupporting

confidence: 93%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…[100][101][102][103] In principle, this allows for the precise regulation of different input pathways via the adjustment of subtype-specific resource pools. [104][105][106][107][108][109] Furthermore, axons of different neuron subtypes target spatially separated regions on the dendritic tree, allowing for pathway-specific local competition. For example, somatostatin-posivite cortical Martinotti cells target the apical dendritic tree of pyramidal cells, while parvalbumin-positive basket cells form synapses closer to the soma, 1 which suggests that afferents of these cell types compete for separate resources pools.…”

Section: Discussionmentioning

confidence: 99%

Synapse-type-specific competitive Hebbian learning forms functional recurrent networks

Eckmann

Gjorgjieva

2022

Preprint

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Cortical networks exhibit complex stimulus-response patterns. Previous work has identified the balance between excitatory and inhibitory currents as a central component of cortical computations, but has not considered how the required synaptic connectivity emerges from biologically plausible plasticity rules. Using theory and modeling, we demonstrate how a wide range of cortical response properties can arise from Hebbian learning that is stabilized by the synapse-type-specific competition for synaptic resources. In fully plastic recurrent circuits, this competition enables the development and decorrelation of inhibition-balanced receptive fields. Networks develop an assembly structure with stronger connections between similarly tuned neurons and exhibit response normalization and surround suppression. These results demonstrate how neurons can self-organize into functional circuits and provide a foundational understanding of plasticity in recurrent networks.

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“…Thus, mossy fiber recruitment of FFI in DG-CA3/CA2 circuits may also depend on increased PV IN excitability as shown for FFI in CA3-CA1 circuits (Campanac et al, 2013). Whether developmental, genetic or epigenetic programs involved in PV IN maturation, excitability and specification of synaptic connectivity are re-used to mediate activity-dependent changes in PV INs excitability and perisomatic inhibition in DG-CA3/CA2 circuits is to be determined (Allaway et al, 2021; Bernard et al, 2022; Dehorter et al, 2015; Exposito-Alonso and Rico, 2022; Favuzzi et al, 2019; Li et al, 2011; Uezu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

Sahay

Shi

Alipio

2023

Preprint

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Heterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1a Dyrk1a gene define a syndromic form of Autism Spectrum Disorder. The synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which Dyrk1a recruits feed-forward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, Ablim3, as a synaptic substrate of Dyrk1a. We demonstrate that Ablim3 downregulation in dentate granule cells of adult hemizygous Dyrk1a mice is sufficient to restore PV IN mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult hemizygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting Dyrk1a synaptic and circuit substrates as enhancers of Dyrk1a function harbors potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.

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Cortical wiring by synapse type–specific control of local protein synthesis

Cited by 34 publications

References 75 publications

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Synapse-type-specific competitive Hebbian learning forms functional recurrent networks

An inhibitory circuit-based enhancer of Dyrk1a function reversesDyrk1a-associated impairment in social recognition

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