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Persistent anion conductances through GABAA receptors (GABAAR) are important modulators of neuronal excitability. However, it is currently unknown how the amplitudes of these currents vary amongst different cell types in the human neocortex, particularly amongst diverse GABAergic interneurons. We have recorded 101 interneurons in and near layer 1 from cortical tissue surgically resected from both male and female patients, visualised 84 of them and measured tonic GABAAR currents in 48 cells with an intracellular [Cl-] of 65 mM and in the presence of 5 µM GABA. We compare these tonic currents amongst five groups of interneurons divided by firing properties and four types of interneuron defined by axonal distributions; rosehip, neurogliaform, stalked-bouton, layers 2-3 innervating and a pool of other cells. Interestingly, the rosehip cell, a type of interneuron only described thus far in human tissue, and layers 2-3 innervating cells exhibit larger tonic currents than other layer 1 interneurons, such as neurogliaform and stalked-bouton cells; the latter two groups showing no difference. The positive allosteric modulators of GABAARs allopregnanolone and DS2 also induced larger current shifts in the rosehip and layer 2-3 innervating cells, consistent with higher expression of the δ-subunit of the GABAAR in these neurons. We have also examined how patient parameters, such as age, seizures, type of cancer and anticonvulsant treatment may alter tonic inhibitory currents in human neurons. The cell type specific differences in tonic inhibitory currents could potentially be used to selectively modulate cortical circuitry.Significance statementTonic currents through GABAA receptors are a potential therapeutic target for a number of neurological and psychiatric conditions. Here we show that these currents in human cerebral cortical GABAergic neurons display cell-type specific differences in their amplitudes which implies differential modulation of their excitability. Additionally, we examine whether the amplitudes of the tonic currents measured in our study show any differences between patient populations, finding some evidence that age, seizures, type of cancer, and anticonvulsant treatment may alter tonic inhibition in human tissue. These results advance our understanding of how pathology affects neuronal excitability and could potentially be used to selectively modulate cortical circuitry.

Original publication

DOI

10.1523/JNEUROSCI.0175-21.2021

Type

Journal article

Journal

J Neurosci

Publication Date

15/10/2021