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Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus.

ABSTRACT: The modifiability of neuronal response plasticity is called "metaplasticity." In suppressing synaptic inhibition and facilitating induction of long-term excitatory synaptic plasticity, endocannabinoids (eCBs) act as agents of metaplasticity. We now report the discovery of a calcium-dependent mechanism that regulates eCB mobilization by metabotropic glutamate receptor (mGluR) activation. The switch-like mechanism primes cells to release eCBs and requires a transient rise in intracellular Ca2+ concentration ([Ca2+]i) but not concurrent activation of mGluRs. Conversely, short-term, [Ca2+]i-dependent eCB release can be persistently enhanced by mGluR activation. Hence, eCBs are also objects of metaplasticity, subject to higher levels of physiological control.

SUBMITTER: Edwards DA

PROVIDER: S-EPMC2409138 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus.

Edwards David A DA Zhang Longhua L Alger Bradley E BE

Proceedings of the National Academy of Sciences of the United States of America 20080603 23

The modifiability of neuronal response plasticity is called "metaplasticity." In suppressing synaptic inhibition and facilitating induction of long-term excitatory synaptic plasticity, endocannabinoids (eCBs) act as agents of metaplasticity. We now report the discovery of a calcium-dependent mechanism that regulates eCB mobilization by metabotropic glutamate receptor (mGluR) activation. The switch-like mechanism primes cells to release eCBs and requires a transient rise in intracellular Ca2+ con ...[more]

PMID: 18523004

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Project description:The possibility that mechanisms of synaptic modulation differ between males and females has far-reaching implications for understanding brain disorders that vary between the sexes. We found recently that 17β-estradiol (E2) acutely suppresses GABAergic inhibition in the hippocampus of female rats through a sex-specific estrogen receptor α (ERα), mGluR, and endocannabinoid-dependent mechanism. Here, we define the intracellular signaling that links ERα, mGluRs, and endocannabinoids in females and identify where in this pathway males and females differ. Using a combination of whole-cell patch-clamp recording and biochemical analyses in hippocampal slices from young adult rats, we show that E2 acutely suppresses inhibition in females through mGluR1 stimulation of phospholipase C, leading to inositol triphosphate (IP3) generation, activation of the IP3 receptor (IP3R), and postsynaptic endocannabinoid release, likely of anandamide. Analysis of sex differences in this pathway showed that E2 stimulates a much greater increase in IP3 levels in females than males, whereas the group I mGluR agonist DHPG increases IP3 levels equivalently in each sex. Coimmunoprecipitation showed that ERα-mGluR1 and mGluR1-IP3R complexes exist in both sexes but are regulated by E2 only in females. Independently of E2, a fatty acid amide hydrolase inhibitor, which blocks breakdown of anandamide, suppressed >50% of inhibitory synapses in females with no effect in males, indicating tonic endocannabinoid release in females that is absent in males. Together, these studies demonstrate sex differences in both E2-dependent and E2-independent regulation of the endocannabinoid system and suggest that manipulation of endocannabinoids in vivo could affect physiological and behavioral responses differently in each sex.Significance statementMany brain disorders vary between the sexes, yet the degree to which this variation arises from differential experience versus intrinsic biological sex differences is unclear. In this study, we demonstrate intrinsic sex differences in molecular regulation of a key neuromodulatory system, the endocannabinoid system, in the hippocampus. Endocannabinoids are involved in diverse aspects of physiology and behavior that involve the hippocampus, including cognitive and motivational state, responses to stress, and neurological disorders such as epilepsy. Our finding that molecular regulation of the endocannabinoid system differs between the sexes suggests mechanisms through which experiences or therapeutics that engage endocannabinoids could affect males and females differently.

Dataset Information

Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus.

Publications

Metaplastic control of the endocannabinoid system at inhibitory synapses in hippocampus.

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