| Original language | English (US) |
|---|---|
| Pages (from-to) | 595-596 |
| Number of pages | 2 |
| Journal | Biological psychiatry |
| Volume | 87 |
| Issue number | 7 |
| DOIs |
|
| State | Published - Apr 1 2020 |
| Externally published | Yes |
ASJC Scopus subject areas
- Biological Psychiatry
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In: Biological psychiatry, Vol. 87, No. 7, 01.04.2020, p. 595-596.
Research output: Contribution to journal › Comment/debate › peer-review
TY - JOUR
T1 - Arrested Development
T2 - A Story of How Perinatal Cannabinoids Affect the Maturation of the Prefrontal Cortex
AU - Winters, Nathan D.
AU - Patel, Sachin
N1 - Funding Information: This work was supported by National Institutes of Health Grant Nos. MH107435 and AA26186 (to SP). Funding Information: The authors use electrophysiological recordings in acute brain slices prepared from rat pups at three developmental time points: postnatal day 9 (P09) to P10, P15 to 16, or P20 (Figure 1A). In relation to human neurodevelopment, the P09 to P10 time point corresponds to the third trimester of human pregnancy, P15 to 16 corresponds to immediately after birth, and P20 corresponds to early life and feeding during maternal lactation (4,5). In control pups that had no cannabinoid exposure, cell-attached recordings from medial prefrontal cortex neurons demonstrated that GABAAR activation exerted an excitatory effect on cell firing at P09 to P10, with an inhibitory effect present at P15 onward. In contrast, in slices from cannabinoid-exposed pups (WIN 55,212-2 or THC), GABAA activation remained excitatory through P15 to P16, in effect delaying the emergence of the inhibitory switch until P20 (Figure 1B). Coinjection of the CB1 receptor antagonist AM-251 prevented the effects of WIN 55,212-2, indicating that CB1 activation mediates this effect. Using single-channel recordings of GABAARs, this effect was confirmed to be due to a delay in the hyperpolarization of the Cl? reversal potential that results from the flipping of the Cl? concentration gradient. To further validate the mechanism, biochemical analyses confirmed an associated delay in the canonical elevation of KCC2 expression levels at both the messenger RNA and the protein level that normalized by P20 in cannabinoid-exposed pups. This series of experiments collectively supports a model in which overengagement of the endocannabinoid system, by exogenous THC, for example, during early brain development delays the canonical mechanisms responsible for the GABA polarity switch by retarding the necessary upregulation of KCC2. Importantly, antagonism of NKCC1 (sodium-potassium-chloride transporter), which declines during development and contributes to the physiological developmental GABA switch, corrected the delayed GABA switch in cannabinoid-treated pups.This work was supported by National Institutes of Health Grant Nos. MH107435 and AA26186 (to SP). SP is scientific consultant for H. Lundbeck A/S, Psy Therapeutics, and Sophran Therapeutics. SP has received research support from H. Lundbeck A/S in the past 3 years. NDW reports no biomedical financial interests or potential conflicts of interest.
PY - 2020/4/1
Y1 - 2020/4/1
UR - http://www.scopus.com/inward/record.url?scp=85080027575&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85080027575&partnerID=8YFLogxK
U2 - 10.1016/j.biopsych.2019.12.011
DO - 10.1016/j.biopsych.2019.12.011
M3 - Comment/debate
C2 - 32164915
AN - SCOPUS:85080027575
SN - 0006-3223
VL - 87
SP - 595
EP - 596
JO - Biological psychiatry
JF - Biological psychiatry
IS - 7
ER -