Adolescent chronic mild stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plasticity.
- Authors
- Reich, C G; Mihalik, G R; Iskander, A N; Seckler, J C; Weiss, M S
- Year
- 2013
- Journal
- Neuroscience
- PMID
- 24035826
- DOI
- 10.1016/j.neuroscience.2013.08.066
- PMCID
- PMC3827785
Endocannabinoids (eCBs) are involved in the stress response and alterations in eCB signaling may contribute to the etiology of mood disorders. Exposure to chronic mild stress (CMS), a model of depression, produces downregulation of the cannabinoid 1 (CB1) receptor in the hippocampus of male rats. However, it is unknown how this stress-induced change in CB1 levels affects eCB-mediated neurotransmission. In vitro, field potential recordings from CMS-exposed (21-days) rats were performed to assess the effects of stress on eCB-regulated glutamatergic neurotransmission in/on hippocampal area CA1. We observed that application of the CB1 agonist, WIN 55,212-5 (1 μM), in stress animals resulted in a ∼135% increase in excitatory neurotransmission, whereas CB1 activation in non-stress animals leads to a ∼30% decrease. However, during blockade of GABA(A) neurotransmission with picrotoxin, CB1 activation yielded a ∼35% decrease in stress animals. These findings indicate that CMS does not directly affect glutamatergic neurotransmission. Rather, CMS sensitizes CB1 function on GABAergic terminals, leading to less inhibition and an increase in excitatory neurotransmission. This finding is reinforced in that induction of weak long-term-potentiation (LTP) is enhanced in CMS-exposed animals compared to controls and this enhancement is CB1-dependent. Lastly, we observed that the LTP-blocking property of WIN 55,212-5 shifts from being glutamate-dependent in non-stress animals to being GABA-dependent in stress animals. These results effectively demonstrate that CMS significantly alters hippocampal eCB-mediated neurotransmission and synaptic plasticity.
CB1 activation in chronic stress animals enhances CA1 excitatory neurotransmissiona) Application of the CB1 agonist WIN (1 μM) decreases fEPSP magnitude in non-stress control animals, but increases magnitude in stress animals. b) The CB1 antagonist prevents the WIN effect in both non-stress and stress animals. In both figures, the top row displays raw traces of example experiments and the bottom shows time course of averaged experiments.
Blocking GABA(A) neurotransmission leads to a decrease in CB1-mediated CA1 excitatory neurotransmission in chronic stress animalsContinuous application of the GABA(A) antagonist picrotoxin (100 μM) reverses the WIN-enhancement of fEPSP magnitude in slices from stress animals. Thus, in picrotoxin, WIN produces a similar decrease in glutamatergic neurotransmission as observed in non-stress slices. Application of AM251 prevents this decrease, confirming that WIN is activating CB1.
WIN Summarya) Bar graph summarizing the WIN experiments. * = significant difference compared to the non-stress group; # = significant difference compared to the stress group; p < 0.05. b) fEPSP amplitude vs. stimulation intensity demonstrates that CMS did not affect basal neurotransmission compared to non-stress controls.
Weak TBS stimulation produces enhanced LTP in CMS animalsa) LTP magnitude is significantly enhanced in stress compared to non-stress animals. b) AM51 prevents LTP enhancement in stress animals. Top: Raw traces of sample experiments; Middle and Bottom Left: time course of average experiments; Middle and Bottom Right: summary graph. * = significant differences compared to baseline; # = significant differences between non-stress and stress, and between stress and stress+AM251; p < 0.05.
Pre-treatment with WIN blocks LTP induction in both stress and non-stress animalsa) Pre-incubation with WIN impairs LTP in slices from CMS animals and application of picrotoxin (50 μM) rescues this deficit. b) Pre-incubation with WIN impairs LTP in slices from non-stress animals but application of picrotoxin does not prevent this deficit. Top: Raw traces of sample experiments; Middle and Bottom Left: time course of average experiments; Middle and Bottom Right: summary graph. * = significant differences compared to baseline; # = significant differences compared to either the stress_WIN group or the non-stress_WIN, respectively; p < 0.05.
Summary of WIN-LTP experiments* = significant difference compared to the non-stress group, ^ = significant difference compared to the stress group, # = significant differences between stress and stress_WIN_PTX; p < 0.05.
LTP is impaired via Strong TBS stimulation in CMS slicesTime course of averaged experiments showing that LTP magnitude is significantly lower in slices from stress animals compared to non-stress slices.
CMS alters CB1-mediated LTP induction in CA1The diagram illustrates how the hypothesized changes in CB1 signalling affect the gating of LTP. Top, Left: a simplified model of the hippocampal CA1 stratum radiatum during basal (non-stress) conditions). Note that CB1 on both glutamatergic and GABAergic (CCK) terminals and that there is a higher density of receptors on GABAergic compared to glutamatergic terminals. Bottom, Left: Following CMS exposure, there is no effect on glutamatergic-CB1 function; although a gain in GABAergic-CB1 function is suggested. This model assumes that CMS also yields a reduction in GABAergic-CB1 density, hence less but larger receptors are illustrated. Right: Summary of findings from both basal and stress conditions. Please see text for a more thorough discussion.
| Name | Type |
|---|---|
| 21-day chronic restraint stress protocol local | cohort |
| 2-AG | drug |
| 2-arachidonoylglycerol | drug |
| acute stress | phenotype |
| Adult male local | cohort |
| AEA | drug |
| AM251 | drug |
| AMPA receptor | drug |
| amygdala | anatomy |
| anandamide | drug |
| animals | cohort |
| anxiety | phenotype |
| artificial cerebrospinal fluid | drug |
| basal neurotransmission local | phenotype |
| brain | anatomy |
| CA1 | anatomy |
| CA1/subiculum local | anatomy |
| CA3 | anatomy |
| CaCl2 | drug |
| calcium | drug |
| CB1 agonists local | drug |
| CB1 receptor | drug |
| Cck | gene |
| CCK‑GABAergic terminals local | drug |
| chronic mild stress local | phenotype |
| Chronic mild stress local | cohort |
| Chronic mild stress local | phenotype |
| chronic mild stress protocol local | cohort |
| chronic restraint stress local | cohort |
| chronic restraint stress local | phenotype |
| Chronic restraint stress local | cohort |
| Chronic restraint stress local | phenotype |
| chronic stress | phenotype |
| CMS local | cohort |
| CMS local | phenotype |
| CMS animals local | cohort |
| CMS exposure local | drug |
| CMS protocol local | cohort |
| CMS protocol local | drug |
| Cnr1 | gene |
| CNR2 | gene |
| CO2 | drug |
| corticosterone | drug |
| CRS local | cohort |
| CRS protocol local | cohort |
| decreased body weight gain local | phenotype |
| depolarization-induced suppression of inhibition | phenotype |
| Depolarization-induced-suppression of inhibition local | phenotype |
| depression | phenotype |
| dimethyl sulfoxide | drug |
| dorsal hippocampus | anatomy |
| endocannabinoids | drug |
| endocannabinoid signaling local | phenotype |
| Endocannabinoid signaling local | phenotype |
| endocannabinoid system | drug |
| fear conditioning | phenotype |
| feedback inhibition of HPA local | phenotype |
| female animals local | cohort |
| fEPSP | phenotype |
| fEPSP amplitude local | phenotype |
| fEPSP excitability local | phenotype |
| GABA | phenotype |
| GABA(A) receptor local | drug |
| GABA_A receptor local | phenotype |
| GABAA receptor | drug |
| GABA(A) receptors local | drug |
| GABAergic CB1 function local | phenotype |
| GABAergic terminals local | anatomy |
| glucocorticoid | drug |
| Glucocorticoid circadian rhythm local | phenotype |
| glucocorticoid receptors local | drug |
| glucocorticoids | drug |
| glucose | drug |
| glutamate | drug |
| glutamatergic terminals local | anatomy |
| habituation of the stress response local | phenotype |
| halothane | drug |
| Hippocampal-dependent cognitive function local | phenotype |
| hippocampus | anatomy |
| HPA activity | phenotype |
| HPA axis | anatomy |
| hypothalamic-pituitary-adrenal axis | anatomy |
| hypothalamus | anatomy |
| inhibition of HPA axis local | phenotype |
| Juvenile rats local | cohort |
| KCl | drug |
| learning and memory | phenotype |
| long-term potentiation | phenotype |
| LTP | phenotype |
| LTP inhibition local | phenotype |
| major depressive disorder | phenotype |
| male animals local | cohort |
| male rats | cohort |
| marijuana | phenotype |
| medial prefrontal cortex | anatomy |
| MgSO4 | drug |
| Mid-adolescence to young adulthood local | cohort |
| mutant mice deficient in CNR1 local | cohort |
| NaH2PO4 | drug |
| NaHCO3 | drug |
| NMDA receptor | drug |
| non‑habituating activation of the HPA local | phenotype |
| Non-hippocampal fear conditioning local | phenotype |
| Non-stress local | cohort |
| non-stress animals local | cohort |
| non‑stress animals local | cohort |
| Non-stress animals local | cohort |
| non-stress cohort local | cohort |
| non-stress slices local | cohort |
| Non-stress WIN local | cohort |
| Non-stress WIN PTX local | cohort |
| NS_WIN local | cohort |
| NS_WIN_PTX local | cohort |
| nucleus accumbens | anatomy |
| oxygen | drug |
| picrotoxin | drug |
| Post-Traumatic Stress Disorder | phenotype |
| prefrontal cortex | anatomy |
| Rat adolescence local | cohort |
| reduced sucrose preference local | phenotype |
| Schaffer collateral local | anatomy |
| Sprague-Dawley rats | cohort |
| sTBS local | phenotype |
| stratum radiatum | anatomy |
| stress | phenotype |
| stress animals local | cohort |
| Stress animals local | cohort |
| stress cohort local | cohort |
| Stress WIN local | cohort |
| Stress WIN PTX local | cohort |
| striatum | anatomy |
| S_WIN local | cohort |
| trace fear conditioning | phenotype |
| ventral hippocampus | anatomy |
| ventral striatum | anatomy |
| ventral subiculum | anatomy |
| WIN 55,212-2 | drug |
| WIN55,212-2 | drug |
| WIN 55,212-5 local | drug |
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