¹Institute of Molecular Physiology and Genetics, Centre of Biosciences SAS, Department of Biophysics and Electrophysiology, Bratislava, Slovakia, ²Institure of Experimental Endocrinology, Biomedical Research Center, SAS, Department of Neuroscience, Bratislava, Slovakia

Background: Transforming growth factor beta 1 (TGF-β1) is a multifunctional cytokine that regulates neural cell growth, differentiation, and apoptosis (Massagué, Annu Rev Cell Biol 6:597, 1990). Recent studies have explored its involvement in the central nervous system, particularly in the therapeutic effect of arketamine, the (R)-enantiomer of ketamine, which exhibits rapid and sustained antidepressant action with fewer dissociative side effects than ketamine (Wei et al., Mol Psychiatry 27:559, 2022). It was observed in an animal model of depression that the abnormalities in TGF-β1 signaling contribute to cognitive deficit associated with depressive-like behavior (Yu et al., Int J Neuropsychopharmacol 14:303-17, 2011), and that intranasal administration of TGF-β1 in rodents elicits antidepressant-like effects (Wei Y et al., Eur Neuropsychopharmacol 50:55-63, 2021).

Aims & Objectives: This study aimed to test the hypothesis that the antidepressant-like effects of TGF-β1 are mediated, at least partially, through the mechanism involving dopaminergic, noradrenergic or serotonergic (5-HT) pathways.

Method: Adult male Wistar rats weighing 250-350g were briefly sedated with isoflurane and intranasally administered TGF-β1 (0,01 mg/kg) or vehicle. One hour after TGF-β1 administration, the rats were anesthetized with chloral hydrate (0.4 g/kg, i.p.). Borosilicate electrodes filled with 2M NaCl were stereotaxically inserted into the ventral tegmental area (VTA), locus coeruleus (LC) and dorsal raphe nucleus (DRN). Dopaminergic, noradrenergic, and 5-HT neurons were identified according to the waveform of their action potentials and mode of their generation (Grinchii et al., Mol Psychiatry 27:4861–4868, 2022) and recorded. To examine whether TGF-β1 modulates the excitability of noradrenergic neurons via a mechanism involving extracellular noradrenaline, the excitability of noradrenergic neurons, in some animals, was assessed after the noradrenaline depletion by fusaric acid (40 mg/kg), administered by two i.p. injections of 40 mg/kg six and four hours before the electrophysiological assessments (Weinshenker D et al., J Neurochem 105:471–483, 2008). To assess whether the putative effect of TGF-β1 on noradrenergic neurons is mediated via the TGFβ1R1 receptor, the selective antagonist of this receptor, LY2109761 (0,033 mg/kg), was administered intro the lateral cerebral ventriculi (5μl, in 10 doses, i.c.v.), one hour prior to the electrophysiological recordings.

Results: We found that the pre-treatment with TGF-β1 did not alter the firing activity of dopaminergic or 5-HT neurons. With respect to the noradrenergic neurons, in fusaric acid-naïve rats, TGF-β1 decreased their mean spontaneous firing rate, frequency of the burst firing, percent of spikes occurring in the bursts, and mean number of spikes in burst. In noradrenaline-depleted rats, however, TGF-β1 did not alter the excitability of noradrenergic neurons. LY2109761 had an opposite, stimulating effect on the firing rate of noradrenergic neurons.

Discussion & Conclusions: In can be concluded that acute nasal administration of TGF-β1 inhibited noradrenergic neurons of the LC, via a mechanism involving TGFβ1R1. An increase in extracellular noradrenaline levels and activation of α₂-adrenoceptors might be a mechanism underlying the inhibitory effect of TGF-β1 on the firing activity of noradrenergic neurons. The putative ability of TGF-β1 might be responsible for the pro-cognitive effect in animal model of depression.
This study was supported by the grants APVV-20-0202, APVV-24-0131, VEGA-2/0045/24, and VEGA- 2/0126/26