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Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids


Neocortical GABA-containing interneurons form complex functional networks responsible for feedforward and feedback inhibition and for the generation of cortical oscillations associated with several behavioural functions1,2. We previously reported that fast-spiking (FS), but not low-threshold-spiking (LTS), neocortical interneurons from rats generate a fast and precise self-inhibition mediated by inhibitory autaptic transmission3. Here we show that LTS cells possess a different form of self-inhibition. LTS, but not FS, interneurons undergo a prominent hyperpolarization mediated by an increased K+-channel conductance. This self-induced inhibition lasts for many minutes, is dependent on an increase in intracellular [Ca2+] and is blocked by the cannabinoid receptor antagonist AM251, indicating that it is mediated by the autocrine release of endogenous cannabinoids. Endocannabinoid-mediated slow self-inhibition represents a powerful and long-lasting mechanism that alters the intrinsic excitability of LTS neurons, which selectively target the major site of excitatory connections onto pyramidal neurons; that is, their dendrites4,5,6,7. Thus, modulation of LTS networks after their sustained firing will lead to long-lasting changes of glutamate-mediated synaptic strength in pyramidal neurons, with consequences during normal and pathophysiological cortical network activities.

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Figure 1: SSI occurs in LTS, not FS, neocortical interneurons.
Figure 2: Low firing frequencies induce SSI, which reflects an increased membrane conductance.
Figure 3: Intracellular increases in [Ca2+] through voltage-dependent Ca2+ channels are required for the induction of SSI in LTS cells.
Figure 4: SSI is mediated by endocannabinoids.


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We thank I. Parada for assistance during these experiments, and J. Krey for discussions. This work was supported by grants from the National Institute of Neurological Diseases and Stroke and the Pimley Research Fund.

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Correspondence to David A. Prince.

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Supplementary information

Supplementary Table

LTS, but not FS interneurons decrease their firing frequency during SSI induction. (DOC 26 kb)

Supplementary Figure 1

LTS but not FS neocortical interneurons contain the neuropeptide CCK. (DOC 452 kb)

Supplementary Figure 2

In LTS interneurons the GIRK channel blocker Ba2+reverses both the hyperpolarization and the conductance change associated with SSI while not affecting baseline membrane potential or gm before SSI induction. (DOC 329 kb)

Supplementary Figure 3

The endocannabinoid receptor blocker AM251 applied to LTS interneurons after SSI induction reverses both membrane potential and gm, indicating a persistent CB1 receptor signaling during SSI. (DOC 352 kb)

Supplementary Figure 4

In the presence of the Na+ channel-blocker tetrodotoxin, SSI can be evoked in LTS interneurons by direct depolarization, indicating that Na+ channels are not sufficient to evoke SSI. (DOC 172 kb)

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Bacci, A., Huguenard, J. & Prince, D. Long-lasting self-inhibition of neocortical interneurons mediated by endocannabinoids. Nature 431, 312–316 (2004).

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