Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior

Abstract

Summary Cortical GABAergic interneurons are generated in large numbers in the ganglionic eminences and migrate into the cerebral cortex during embryogenesis. At early postnatal stages, during neuronal circuit maturation, autonomous and activity-dependent mechanisms operate within the cortex to adjust cell numbers by eliminating naturally occurring neuron excess. Here, we show that when cortical interneurons are generated in aberrantly high numbers—due to a defect in precursor cell proliferation during embryogenesis—extra parvalbumin interneurons persist in the postnatal mouse cortex during critical periods of cortical network maturation. Even though cell numbers are subsequently normalized, behavioral abnormalities remain in adulthood. This suggests that timely clearance of excess cortical interneurons is critical for correct functional maturation of circuits that drive adult behavior.

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

“…It is unclear which neuronal subtypes mediate this effect, as Nkx2.1 Cre lineages populate many areas, including the striatum and ventral forebrain that influence motor behavior (Fu et al, 2014; Hutton et al, 2017; Xu et al, 2008). In future studies, it will be important to investigate how ERK1/2 signaling in CINs influences more complex behaviors (Adler et al, 2019; Chen et al, 2019; Cummings & Clem, 2020; Fu et al, 2014; Kluge et al, 2008; C. Lee et al, 2022; Magno et al, 2021).…”

“…GABA-mediated signals promote the maturation of excitatory neurons, in part via ERK1/2 dependent mechanisms (Cancedda et al, 2007; Obrietan et al, 2002; Peerboom & Wierenga, 2021). Past reports demonstrate that early alterations in CIN number or activity can permanently change circuit architecture and animal behavior (Bitzenhofer et al, 2021; Kaneko et al, 2022; Magno et al, 2021; Tuncdemir et al, 2016). Here, we employed a chemogenetic approach to selectively activate CINs with temporal specificity.…”

Interferon-γ augments GABA release in the developing neocortex via nitric oxide synthase/soluble guanylate cyclase and constrains network activity

“…GABAergic interneurons control critical periods of synaptic plasticity in functional circuits of the cortex (for review Hensch, 2005 ), i.e., enhanced GABAergic transmission prematurely induces such periods ( Fagiolini et al, 2004 ), leading to a mismatch of sensory stimuli and synaptic plasticity. In line with this, transient disturbances of interneuron generation and integration cause long-term behavioral abnormalities—even after cell counts normalize ( Magno et al, 2021 ). On one hand, excitation–inhibition balance is stabilized by GABAergic currents adapting to activity ( Xue et al, 2014 ) but also sensory deprivation may increase GABAergic inhibition ( Maffei et al, 2006 ).…”

Cxcr4 and Ackr3 regulate allocation of caudal ganglionic eminence-derived interneurons to superficial cortical layers

“…If, however, some layers receive less mGE-cINs than finally needed, this may cause a persistent layer-specific reduction, as is the case for SST + mGE-cINs in P30 Ackr3 STA/STA mice (Table S7). Given that a transient increase in the number of mGE-cINs is sufficient to permanently affect cortical function (Magno et al, 2021), it is plausible that transient alterations in the layer-specific distribution of mGE-cINs caused by perturbed Cxcl12-Cxcr4 signaling generate a predisposition to psychiatric disorders (Muraki and Tanigaki, 2015).…”