The forced swimming test is reviewed. This test appears to be suitable for detecting antidepressant activity in rats but not in mice. Difference in experimental procedure may account for the different sensitivity to drugs of the two animal species.

Is the forced swimming test a suitable model for revealing antidepressant activity

Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology. Mouse models of Alzheimer’s disease show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline; driving neurons to oscillate at gamma frequency (40 Hz) reduces levels of amyloid-β peptides. Disrupted gamma rhythms—oscillations in the brain's neuronal circuits at around 20–50 Hz—are hallmarks of various neurological disorders and have been seen in patients with Alzheimer's disease and specific mouse models of the disease. Li-Huei Tsai and colleagues show that gamma oscillations are also disrupted in the 5XFAD mouse model of Alzheimer's disease, and find reduced gamma prior to plaque formation and cognitive decline. Remarkably, by training neurons to oscillate at gamma frequency (40 Hz) in multiple mouse models including APP/PS1 and wild-type mice, amyloid-β peptide levels could be reduced.

/pdf/gamma-frequency-entrainment-attenuates-amyloid-load-and-1133q0v5wr.pdf

Gamma frequency entrainment attenuates amyloid load and modifies microglia

We have previously shown that estradiol causes a twofold rise in dendritic spine density in cultured rat hippocampal neurons, as it doesin vivo. More recently, estrogen receptors have been localized to aspiny inhibitory hippocampal interneurons, indicating that their effect on spiny pyramidal neurons may be indirect. We therefore examined the possibility that estradiol affects spine density by regulating inhibition in cultured hippocampal interneurons. Immunocytochemically, estrogen receptors were found to be co-localized with glutamate decarboxylase (GAD)-positive neurons (∼21% of total neurons in the culture). Exposure of cultures to estradiol for 1 d caused a marked decrease (up to 80%) in the GAD content of the interneurons, measured both by immunohistochemistry and Western blotting. Also, the number of GAD-positive neurons in the cultures decreased to 12% of the total cell population. Moreover, GABAergic miniature IPSCs were reduced in both size and frequency by estradiol, whereas miniature EPSCs increased in frequency. We then mimicked the proposed effects of estradiol by blocking GABA synthesis with mercaptopropionic acid (MA). Cultures treated with MA expressed a dose-dependent decrease in GABA immunostaining that mimicked that seen with estradiol. MA-treated cultures displayed a significant 50% increase in dendritic spine density over controls, similar to that produced by estradiol. These results indicate that estradiol decreases GABAergic inhibition in the hippocampus, which appears to effectively increase the excitatory drive on pyramidal cells, and thus may provide a mechanism for formation of new dendritic spines.

https://www.jneurosci.org/content/jneuro/18/7/2550.full.pdf

Estradiol Increases Dendritic Spine Density by Reducing GABA Neurotransmission in Hippocampal Neurons

This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.

/pdf/neurosteroids-endogenous-role-in-the-human-brain-and-1hh2aadsy0.pdf

Neurosteroids: Endogenous role in the human brain and therapeutic potentials

The role of central serotonergic (5-HT) system dysfunction in the regulation of aggression in both animals and man has been investigated for more than the past two decades. Evidence for reduced central 5-HT in the mediation of aggression comes from both behavioural and correlative studies. Functional reduction and augmentation of 5-HT activity is respectively associated with increased and decreased aggression in various animal models of aggression. While similar studies in man have not been performed, strong and consistent associations between indices reflecting reduced pre-synaptic 5-HT activity and aggression have been reported. Evidence of post-synaptic receptor upregulation in the brains of suicide victims has also been reported leaving the functional status 5-HT activity in such patients an open question. However, reduced neuroendocrine (i.e. prolactin) responses to fenfluramine, a 5-HT uptake inhibitor/releaser, which activates both pre- and post-synaptic sides of the 5-HT synapse, strongly suggest that overall central 5-HT activity is reduced in mood and/or personality disorder patients with history of suicidal and/or impulsive aggressive behaviour. Preliminary data with the 5-HT receptor agonist m-chlorophenylpiperazine further suggest that reduced activity of post-synaptic 5-HT receptors may be an important correlate of impulsive aggressive behaviour. Pharmacological agents with potent 5-HT pre- and/or post-synaptic augmenting effects should be tested clinically to determine their efficacy in the treatment of impulsive aggressive behaviour in psychiatric patients.

Central serotonin and impulsive aggression.

To explore the possible involvement of glucocorticoids in the previously observed anticonvulsive effect of swim stress, mice were, prior to administration of convulsants, subjected to treatments that diminish or enhance plasma corticosterone levels. Aminoglutethimide, the inhibitor of steroid synthesis, failed to modify convulsant doses of picrotoxin, but enhanced threshold doses of pentylenetetrazole producing myoclonus and death, both in unstressed and stressed animals. The same drug prevented the effect of stress on pentylenetetrazole-induced running bouncing clonus (RB clonus) and abolished the appearance of tonic hindlimb extension (THE). Doses of kainic acid producing convulsions and death were not affected by stress, but they were enhanced by aminoglutethimide. Corticosterone administration could not imitate the effect of swim stress. Finasteride, a 5 alpha-reductase inhibitor, did not interfere with the effect of stress on picrotoxin-induced convulsions. Swim stress failed to modify the binding of the convulsant t[3H]-butylbicycloorthobenzoate [3H]TBOB, to washed mouse forebrain membranes. The results confirmed an anticonvulsant effect of swim stress against convulsions produced by GABA-related convulsants, but they do not support the hypothesis suggesting the involvement of glucocorticoids or neurosteroids in this effect.

Anticonvulsive Effect of Swim Stress in Mice

Sex differences in the response of rats to drugs affecting GABAergic transmission

Sex related differences in the response of mice, rats and cats to administration of picrotoxin

Swim stress alters the behavioural response of mice to GABA-related and some GABA-unrelated convulsants.

In light of the numerous but rather conflicting reports on the action of benzodiazepines upon the hypothalamo-hypophyseal-adrenal (HHA) axis activity, the effect of different doses of diazepam (0.1, 1.0 and 10.0 mg/kg) administered 15, 30, 60, 120 and 240 min before decapitation on plasma corticosterone level was studied in rats. While 0.1 mg/kg diazepam had no effect, 1.0 mg/kg diazepam decreased plasma corticosterone levels 30 and 60 min following drug administration. On the other hand, treatment with 10.0 mg/kg diazepam produced an increase in plasma corticosterone levels from 15–120 min following drug administration.

Danka Peričić

Papers

Anticonvulsive Effect of Swim Stress in Mice

Sex differences in the response of rats to drugs affecting GABAergic transmission

Sex related differences in the response of mice, rats and cats to administration of picrotoxin

Swim stress alters the behavioural response of mice to GABA-related and some GABA-unrelated convulsants.

Effect of diazepam on plasma corticosterone levels.