Sensory inputs control the integration of neurogliaform interneurons into cortical circuits

Sensory inputs control the integration of neurogliaform interneurons into cortical circuits De Marco García Priya Tuncdemir Fishell Karayannis

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Sensory inputs control the integration of neurogliaform interneurons into cortical circuits 2015 Nature Neuroscience 10.1038/nn.3946 De-Marco-Garc-a2015-sensory-inputs-control-the-integration-of-ne De-Marco-Garc-a2015-sensory-inputs-control-the-integration-of-ne.txt, the project's staged copy a2f70857e1182f55b605b1386094b31e03f83504 not-redistributable neuroscience

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them how Reelin-expressing neurogliaform interneurons acquire their pattern of afferent connectivity during the first postnatal week Quotation withheld because this record is not cleared for redistribution. what regulates the balance between thalamic and intracortical inputs onto developing superficial interneurons Quotation withheld because this record is not cleared for redistribution. shows superficial Reelin interneurons receive direct thalamic input during development, and that NMDA receptor signalling through it sets the ratio of thalamic to intracortical connectivity Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. cortical interneuron circuit integration Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Developing interneurons discriminate between otherwise similar glutamatergic afferents according to which postsynaptic receptor subtype those afferents engage Quotation withheld because this record is not cleared for redistribution. mechanisms NR2B-containing NMDA receptors are preferentially allocated to the dendritic postsynaptic sites that receive thalamic input, giving ascending afferents a privileged signalling channel Quotation withheld because this record is not cleared for redistribution. mechanisms NMDA receptor activation drives the interneuron's integration into the nascent circuit, so that losing it both stunts the arbor and shifts the balance of afferents toward local cortical sources Quotation withheld because this record is not cleared for redistribution. sparse electroporation plus focal rabies injection yields one starter cell per brain, so the traced inputs belong to a single identified interneuron Quotation withheld because this record is not cleared for redistribution. anatomical tracing is confirmed functionally by optogenetic mapping with TTX and 4AP, isolating monosynaptic responses Quotation withheld because this record is not cleared for redistribution. the requirement is timed: removing the receptor at P3 reproduces the defect and at P6 does not, placing the critical window between them Quotation withheld because this record is not cleared for redistribution. the effect is subunit-specific - NR2B-containing receptors are required, NR2A-containing ones are not Quotation withheld because this record is not cleared for redistribution. AMPA receptor signalling remains intact and is not sufficient: the cells still fail to develop axons or integrate Quotation withheld because this record is not cleared for redistribution. the total input count is preserved while its composition flips, so this is reallocation rather than loss Quotation withheld because this record is not cleared for redistribution. The authors could not rule out that some cortical glutamatergic signalling survived their viral tetanus-toxin blockade of intracortical input. what this limits: the completeness of the silencing: WE COULD NOT FORMALLY EXCLUDE THE POSSIBILITY THAT RESIDUAL CORTICAL GLUTAMATERGIC SIGNALING TO Re+ INTERNEURONS PERSISTED Quotation withheld because this record is not cleared for redistribution. The complete-intracortical-blockade genotype yielded very few animals, so a second mouse line had to be generated to enlarge the sample. what this limits: the complete-blockade analysis: IN AN EFFORT TO INCREASE THE SAMPLE SIZE FOR THIS ANALYSIS, WE GENERATED MICE containing a second allele combination, because the first genotype was too rare Quotation withheld because this record is not cleared for redistribution. the absence of neuromodulatory input is overridden by inference from the authors' own prior work, which says it must appear eventually what this limits: the claim that these cells lack neuromodulatory input: WE DID NOT OBSERVE APPRECIABLE INPUTS ... FROM ASCENDING NEUROMODULATORY FIBERS, supported by SUPPLEMENTARY FIG. 3 AND DATA NOT SHOWN Quotation withheld because this record is not cleared for redistribution. interneuron-to-interneuron connectivity did not change significantly, with only three mutant animals what this limits: the interneuron-to-interneuron connectivity comparison: NOT SIGNIFICANTLY CHANGED (CTRL: 27% +/- 6 VERSUS 42% +/- 4, P = 0.103) - a null on a small sample rather than an established absence Quotation withheld because this record is not cleared for redistribution. the cross-species claim about the proportion of these interneurons is explicitly a speculation what this limits: the cross-species reading: Quotation withheld Quotation withheld because this record is not cleared for redistribution. whether VIP interneurons use intrinsic programs or unidentified activity sources is left open what this limits: the generality of the activity-dependence claim: VIP+ INTERNEURONS MAY USE EITHER INTRINSIC GENETIC PROGRAMS OR AS-YET-UNIDENTIFIED SOURCES OF ACTIVITY Quotation withheld because this record is not cleared for redistribution. monosynaptic rabies tracing, adapted to single starter cells and to developmental time points Quotation withheld because this record is not cleared for redistribution. the finding that specific rather than global activity refines connectivity, used as the frame for this result Quotation withheld because this record is not cleared for redistribution. the same rabies-tracing experiment repeated in a LARGER AND DIFFERENT SUBSET of superficial interneurons, including VIP- and calretinin-expressing subtypes eliminates: a bias in the method itself - if rabies tracing simply fails to label some synapse types, the absence of nucleus basalis input onto Re+ interneurons would be an artefact of the tracer rather than a fact about the circuit · outcome: held Quotation withheld because this record is not cleared for redistribution. balance here is a RATIO of afferent sources whose total is conserved - thalamic falls from 60% to 16% while intracortical rises from 14% to 42%, with the same number of presynaptic cells Quotation withheld because this record is not cleared for redistribution. the same glutamatergic input is distinguished not by its transmitter but by which postsynaptic receptor it acts on, which is what lets one afferent source matter and another not Quotation withheld because this record is not cleared for redistribution. Re-positive and VIP-positive interneurons are used throughout as a built-in contrast: every manipulation that impairs one leaves the other intact Quotation withheld because this record is not cleared for redistribution. the absence of cholinergic input is scoped to this age, not to this cell type - the authors expect it to appear later Quotation withheld because this record is not cleared for redistribution. claim_type: mechanism a second reading reaching the same value. Recorded: mechanism — note: a second reading reaching the same value from a different sentence. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: monosynaptic rabies tracing from single starter interneurons, ChR2-assisted circuit mapping, whisker deprivation, and cell-autonomous conditional removal of NMDA receptor subunits a second reading DIFFERING from the recorded value. Recorded: electrophysiology — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. phenomenon: activity-dependent assembly of cortical microcircuits a second reading DIFFERING from the recorded value. Recorded: cortical interneuron circuit integration — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. extends → previous work showing that sensory experience shapes the topography of the sensory cortices (refs 33-37) Quotation withheld because this record is not cleared for redistribution. builds-on → the authors' own preceding study of how dampened excitation affects interneuron positioning and maturation (ref 9) Quotation withheld because this record is not cleared for redistribution. contradicts → the classical view that layer IV is the primary recipient of ascending thalamic sensory input Quotation withheld because this record is not cleared for redistribution. extends → the authors' own earlier finding that Re-positive but not VIP-positive interneurons require activity to mature Quotation withheld because this record is not cleared for redistribution. supports → retinogeniculate work showing that specific activity, not overall activity level, drives afferent refinement Quotation withheld because this record is not cleared for redistribution. supports → published rabies tracing of mature VIP interneurons showing no bias toward thalamic synapses Quotation withheld because this record is not cleared for redistribution. NR2B —distinct-from→ NR2A NR2B NR2A differs in: THE AXIS IS WHICH SUBUNIT'S REMOVAL PRODUCES THE DEFECT. 'thalamocortical synapses use NMDA receptors (NMDARs) containing the NR2B subunit and ... Quotation withheld in Re+ interneurons.' Both subunits are present; only one is load-bearing for the morphology, and the contrast is a loss-of-function result rather than a difference in expression. · strength of the relation: 1 Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED) · AMPAR —distinct-from→ NMDA AMPAR NMDA EVIDENCE CORRECTED: RE-GROUNDED. The old span named only AMPARs. This sentence sets the two against each other in the paper's own construction - 'the contribution of NMDARs VERSUS AMPARs'. — strength of the relation: 0.95 · note: AMPAR signalling is present and explicitly insufficient, which is what makes the requirement receptor-specific rather than activity-general Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span says interneurons failed to develop 'even in the presence of substantial signaling through AMPARs' when NMDARs were removed; distinct-from is implied, not stated. Quotation withheld because this record is not cleared for redistribution. EVIDENCE CORRECTED (RE-GROUNDED) · neurogliaform —distinct-from→ VIP neurogliaform VIP EVIDENCE CORRECTED: RE-GROUNDED. The old span named only VIP. This sentence names both, says 'marked DIFFERENCES in the requirement for activity', and uses 'UNLIKE' between the two cell types. — strength of the relation: 1 · note: the built-in contrast: every manipulation impairing one leaves the other intact Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but this span says Re+ but not VIP+ interneurons were impaired; 'neurogliaform' is not named here, so distinct-from rests on the record's other span. Quotation withheld because this record is not cleared for redistribution. neurogliaform —distinct-from→ VIP neurogliaform VIP differs in: THE AXIS IS WHETHER DEVELOPMENT REQUIRES ACTIVITY. 'We observed marked differences in the requirement for activity in VIP multipolar cells, which were apparently unaffected by attenuated levels of excitation, unlike Re+ neurogliaform cells, whose migration and morphological development were markedly impaired.' Two interneuron classes in the same manipulation, and only one needs the activity - so a study using either alone would conclude the opposite about interneuron development in general. · strength of the relation: 1 · note: RE-GROUNDS another row of this record: the old span named ONE endpoint. Quotation withheld because this record is not cleared for redistribution. AMPAR —distinct-from→ NMDA AMPAR NMDA strength of the relation: 0.95 · note: RE-GROUNDS another row of this record: the old span named ONE endpoint. Quotation withheld because this record is not cleared for redistribution. Mann-Whitney U test Mann-Whitney U test Quotation withheld because this record is not cleared for redistribution. t-test t-test Quotation withheld because this record is not cleared for redistribution. standard error of the mean standard error of the mean Quotation withheld because this record is not cleared for redistribution. p-value p-value Quotation withheld because this record is not cleared for redistribution. unpaired t-test on morphological measures unpaired t-test on morphological measures Quotation withheld because this record is not cleared for redistribution. proportion of presynaptic partners by source proportion of presynaptic partners by source Quotation withheld because this record is not cleared for redistribution. Contrary to the classical view that layer IV is the main recipient of ascending sensory input, Reelin-expressing interneurons in layers I-III receive direct thalamic afferents during the first postnatal week. Quotation withheld because this record is not cleared for redistribution. Whisker deprivation left cortical layering and interneuron migration intact but severely truncated the axons and dendrites of Reelin-expressing interneurons. Quotation withheld because this record is not cleared for redistribution. The results suggest thalamic activity is fundamental to the axo-dendritic development of Re+ interneurons. Quotation withheld because this record is not cleared for redistribution. Blocking intracortical glutamate release, by contrast, left the morphological development of the same interneurons unaffected. Quotation withheld because this record is not cleared for redistribution. Light-evoked NMDAR responses had a larger NR2B component with thalamic (VGlut2-ChR2) than with cortical (Emx1-ChR2) activation. Quotation withheld because this record is not cleared for redistribution. The maturation requirement is specific to NR2B: NR2A-null and AMPA-receptor-blocked interneurons developed normally. Quotation withheld because this record is not cleared for redistribution. The NMDA receptor requirement is confined to a narrow window between postnatal days 3 and 6. Quotation withheld because this record is not cleared for redistribution. Deleting NR1 in these interneurons cut thalamic input from 60% to 16% and raised intracortical pyramidal input from 14% to 42%. Quotation withheld because this record is not cleared for redistribution. superficial Reelin interneurons receive direct thalamic input in the first postnatal week, contrary to the layer IV expectation Quotation withheld because this record is not cleared for redistribution. each interneuron received about 196 presynaptic partners, 56% of them thalamic Quotation withheld because this record is not cleared for redistribution. no appreciable input from dorsal raphe or nucleus basalis was found at this age Quotation withheld because this record is not cleared for redistribution. the same tracing method did find nucleus basalis input to VIP and calretinin interneurons, so the absence is not a method artifact Quotation withheld because this record is not cleared for redistribution. removing NMDA receptors cut thalamic input from 60% to 16% and raised intracortical from 14% to 42% Quotation withheld because this record is not cleared for redistribution. the total number of presynaptic cells did not change Quotation withheld because this record is not cleared for redistribution. the requirement falls between P3 and P6 Quotation withheld because this record is not cleared for redistribution. cortical layering and pyramidal cell distribution were normal despite the interneuron defects Quotation withheld because this record is not cleared for redistribution. cells with rudimentary dendrites nonetheless received exuberant aberrant intracortical innervation Quotation withheld because this record is not cleared for redistribution. VAMP2 VAMP2 Quotation withheld because this record is not cleared for redistribution. critical period critical period Quotation withheld because this record is not cleared for redistribution. chronic bilateral whisker plucking chronic bilateral whisker plucking Quotation withheld because this record is not cleared for redistribution. genetic blockade genetic blockade Quotation withheld because this record is not cleared for redistribution. thalamic afferent connectivity thalamic afferent connectivity Quotation withheld because this record is not cleared for redistribution. intracortical pyramidal cell innervation intracortical pyramidal cell innervation Quotation withheld because this record is not cleared for redistribution. dendritic length dendritic length Quotation withheld because this record is not cleared for redistribution. complexity of axonal arbors complexity of axonal arbors Quotation withheld because this record is not cleared for redistribution. 196 ± 48 — mean number of presynaptic neurons traced to a single Reelin-expressing starter interneuron Quotation withheld because this record is not cleared for redistribution. 56 o 6% — share of traced presynaptic inputs originating in the VPM and POm thalamic nuclei (the ± sign is corrupted in the source text) Quotation withheld because this record is not cleared for redistribution. 30% ... 50% — share of all interneurons that are superficial Reelin- or VIP-expressing cells, in mouse versus human brain Quotation withheld because this record is not cleared for redistribution. −83.89 ± 17.62 pA versus −3.60 ± 3.60 pA — mean intracortically evoked EPSC amplitude in control versus cortex-wide tetanus-toxin (Emx1-TeLC) mice, showing near-complete blockade Quotation withheld because this record is not cleared for redistribution. 190 ± 55 versus 150 ± 47; P = 0.646 — total presynaptic cells per starter cell in control versus NMDA-receptor-ablated interneurons, statistically indistinguishable Quotation withheld because this record is not cleared for redistribution. 60% ± 6 to 16% ± 2 — drop in the thalamic share of afferent connectivity after cell-autonomous NMDA receptor removal Quotation withheld because this record is not cleared for redistribution. 196 plus or minus 48 presynaptic neurons per interneuron, 56% thalamic, 14% local excitatory, 30% interneuron — the normal afferent composition Quotation withheld because this record is not cleared for redistribution. thalamic 60% to 16%, intracortical 14% to 42%, interneuron 27% to 42% (n.s.) — the composition after NMDA receptor removal Quotation withheld because this record is not cleared for redistribution. 190 versus 150 presynaptic cells, p = 0.646 — total input unchanged while composition flipped Quotation withheld because this record is not cleared for redistribution. about 10 ms EPSC latency — checked against prior studies using the same approach Quotation withheld because this record is not cleared for redistribution. about 30% of interneurons in mouse and 50% in human — the proportion of superficial interneurons across species Quotation withheld because this record is not cleared for redistribution.

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