Physical Exercise and Antidepressants Enhance BDNF Targeting in Hippocampal CA3 Dendrites: Further Evidence of a Spatial Code for BDNF Splice Variants

Abstract

Brain-derived neurotrophic factor (BDNF) is encoded by multiple BDNF transcripts, whose function is unclear. We recently showed that a subset of BDNF transcripts can traffic into distal dendrites in response to electrical activity, while others are segregated into the somatoproximal domains. Physical exercise and antidepressant treatments exert their beneficial effects through upregulation of BDNF, which is required to support survival and differentiation of newborn dentate gyrus (DG) neurons. While these DG processes are required for the antidepressant effect, a role for CA1 in antidepressant action has been excluded, and the effect on CA3 neurons remains unclear. Here, we show for the first time that physical exercise and antidepressants induce local increase of BDNF in CA3. Voluntary physical exercise for 28 consecutive days, or 2-week treatment with 10 mg/kg per day fluoxetine or reboxetine, produced a global increase of BDNF mRNA and protein in the neuronal somata of the whole hippocampus and a specific increase of BDNF in dendrites of CA3 neurons. This increase was accounted for by BDNF exon 6 variant. In cultured hippocampal neurons, application of serotonin or norepinephrine (10-50 mM) induced increase in synaptic transmission and targeting of BDNF mRNA in dendrites. The increased expression of BDNF in CA3 dendrites following antidepressants or exercise further supports the neurotrophin hypothesis of antidepressants action and confirms that the differential subcellular localization of BDNF mRNA splice variants provides a spatial code for a selective expression of BDNF in specific subcellular districts. This selective expression may be exploited to design more specific antidepressants.

Functional Role of BDNF Production from Unique Promoters in Aggression and Serotonin Signaling

“…Evidence that different Bdnf transcripts are directed to distinct subcellular compartments following neural activity supports the view that these transcripts serve unique, or only partially overlapping, functions Baj et al, 2012;Baj et al, 2011;Lau et al, 2010;Pattabiraman et al, 2005). In rodents, differential production of Bdnf splice variants has been documented in a number of models of neurological and neuropsychiatric disease and in response to various pharmacological treatments (Dias et al, 2003;Fumagalli et al, 2012;Nair et al, 2007;Zuccato et al, 2001).…”

Expression of BDNF and trkB in the hippocampus of a rat genetic model of vulnerability (Roman low‐avoidance) and resistance (Roman high‐avoidance) to stress‐induced depression

“…There is also growing evidence that antidepressant treatments may exert some of their therapeutic effects by increasing BDNF expression levels and affecting BDNF transcription in the hippocampus. Thus, (i) electroconvulsive brain stimulation, a treatment of choice for medication‐resistant depression, increases the hippocampal contents of BDNF and trkB mRNAs (Altar, Whitehead, Chen, Wörtwein, & Madsen, 2003; Angelucci, Aloe, Jiménez‐Vasquez, & Mathé, 2002; Nibuya et al., 1995), particularly in the dorsal hippocampus (Ploski et al., 2006), (ii) antidepressant treatment rapidly elevates the content of BDNF mature protein via posttranscriptional mechanisms, prevents the stress‐induced decrease in the hippocampal concentration of BDNF mRNA and counteracts the depression‐associated alterations in neural plasticity by normalizing BDNF in the rodent prefrontal cortex and hippocampus (Baj et al., 2012; Kozisek et al., 2008; Musazzi et al., 2009). In keeping with these experimental findings, postmortem samples from clinically depressed patients treated with antidepressant medications show increased BDNF immunoreactivity in the hilus, the dentate gyrus and the supragranular regions of the hippocampus as compared with antidepressant‐untreated controls (Chen, Dowlatshahi, MacQueen, Wang, & Young, 2001).…”

“…Interestingly, it has been shown that different antidepressant treatments, such as physical activity (Baj et al., 2012; Kozisek et al., 2008), the electroconvulsive treatment, and several antidepressant medications (Adachi et al., 2008; Alboni et al., 2010; Baj et al., 2012; Elfving et al., 2010; Kozisek et al., 2008; Marmigère, Givalois, Rage, Arancibia, & Tapia‐Arancibia, 2003) modulate differently the expression of BDNF in specific hippocampal subfields. Therefore, in the present study we evaluated the basal expression of BDNF and trkB in different subregions of the hippocampus of the Roman rat lines.…”

Epigenetic Regulation of BDNF Gene during Development and Diseases

“…For instance, in an adult mouse brain, exon V was highly expressed in the cortex and hippocampus, whereas exon III was detected in all brain regions with similar expression [15]. In addition, exon VI was increased in hippocampal CA3, but not CA1 and dentate gyrus neurons in response to the antidepressant drugs fluoxetine and reboxetine [34]. Furthermore, different stimuli induce Bdnf transcripts.…”