Thalamic inhibitory circuits and network activity development

In the early stages of the central nervous system growth and development, γ-aminobutyric acid (GABA) plays an instructive trophic role for key events including neurogenesis, migration, synaptogenesis, and network formation. These actions are associated with increased concentration of chloride ions in immature neurons [(Cl−)i] that determines the depolarizing strength of ion currents mediated by GABAA receptors, a ligand-gated Cl− permeable ion channel. During neuron maturation the (Cl−)i progressively decreases leading to weakening of GABA induced depolarization and enforcing GABA function as principal inhibitory neurotransmitter. A neuron restricted potassium-chloride co-transporter KCC2 is a key molecule governing Cl− extrusion and determining the resting level of (Cl−)i in developing and mature mammalian neurons. Among factors controlling the functioning of KCC2 and the maturation of inhibitory circuits, is Smoothened (Smo), the transducer in the receptor complex of the developmental protein Sonic Hedgehog (Shh). Too much or too little Shh-Smo action will have mirror effects on KCC2 stability at the neuron membrane, the GABA inhibitory strength, and ultimately on the newborn susceptibility to neurodevelopmental disorders. Both canonical and non-canonical Shh-Smo signal transduction pathways contribute to the regulation of KCC2 and GABAergic synaptic activity. In this review, we discuss the recent findings of the action of Shh-Smo signaling pathways on chloride ions homeostasis through the control of KCC2 membrane trafficking, and consequently on inhibitory neurotransmission and network activity during postnatal development.

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Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

10.1101/2020.02.24.963041 ◽

2020 ◽

Author(s):

Javier Zorrilla de San Martin ◽

Cristina Donato ◽

Jérémy Peixoto ◽

Andrea Aguirre ◽

Vikash Choudhary ◽

...

Keyword(s):

Down Syndrome ◽

Prefrontal Cortex ◽

Cognitive Deficits ◽

Pyramidal Neurons ◽

Phase Locking ◽

Network Activity ◽

Inhibitory Circuits ◽

Network Oscillations ◽

Fast Spiking

AbstractDown syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration of their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying of cognitive dysfunctions in DS.

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Alterations of specific cortical GABAergic circuits underlie abnormal network activity in a mouse model of Down syndrome

eLife ◽

10.7554/elife.58731 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Javier Zorrilla de San Martin ◽

Cristina Donato ◽

Jérémy Peixoto ◽

Andrea Aguirre ◽

Vikash Choudhary ◽

...

Keyword(s):

Down Syndrome ◽

Prefrontal Cortex ◽

Cognitive Deficits ◽

Pyramidal Neurons ◽

Phase Locking ◽

Network Activity ◽

Inhibitory Circuits ◽

Network Oscillations ◽

Fast Spiking

Down syndrome (DS) results in various degrees of cognitive deficits. In DS mouse models, recovery of behavioral and neurophysiological deficits using GABAAR antagonists led to hypothesize an excessive activity of inhibitory circuits in this condition. Nonetheless, whether over-inhibition is present in DS and whether this is due to specific alterations of distinct GABAergic circuits is unknown. In the prefrontal cortex of Ts65Dn mice (a well-established DS model), we found that the dendritic synaptic inhibitory loop formed by somatostatin-positive Martinotti cells (MCs) and pyramidal neurons (PNs) was strongly enhanced, with no alteration in their excitability. Conversely, perisomatic inhibition from parvalbumin-positive (PV) interneurons was unaltered, but PV cells of DS mice lost their classical fast-spiking phenotype and exhibited increased excitability. These microcircuit alterations resulted in reduced pyramidal-neuron firing and increased phase locking to cognitive-relevant network oscillations in vivo. These results define important synaptic and circuit mechanisms underlying cognitive dysfunctions in DS.

Download Full-text