BDNF impact on synaptic dynamics: extra or intracellular long-term release differently regulates cultured hippocampal synapses

Abstract

Brain Derived Neurotrophic Factor (BDNF) signalling contributes to the formation, maturation and plasticity of Central Nervous System (CNS) synapses. Acute exposure of cultured brain circuits to BDNF leads to up-regulation of glutamatergic neuro-transmission, by the accurate tuning of pre and post synaptic features, leading to structural and functional synaptic changes. Chronic BDNF treatment has been comparatively less investigated, besides it may represent a therapeutic option to obtain rescue of post-injury alterations of synaptic networks. In this study, we used a paradigm of BDNF long-term (4 days) incubation to assess in hippocampal neurons in culture, the ability of such a treatment to alter synapses. By patch clamp recordings we describe the augmented function of excitatory neurotransmission and we further explore by live imaging the presynaptic changes brought about by long-term BDNF. In our study, exogenous long-term BDNF exposure of post-natal neurons did not affect inhibitory neurotransmission. We further compare, by genetic manipulations of cultured neurons and BDNF release, intracellular overexpression of this neurotrophin at the same developmental age. We describe for the first-time differences in synaptic modulation by BDNF with respect to exogenous or intracellular release paradigms. Such a finding holds the potential of influencing the design of future therapeutic strategies.

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

“…This neuroplastic effect is probably achieved through the activation of intracellular-signaling cascades [ 173 , 174 ]. Recent data suggest that intracellular overexpression of BDNF in hippocampal developing neurons induces maturation of excitatory and inhibitory synapses, with respect to exogenous application of BDNF [ 175 ]. BDNF mice lacking BDNF die during the second postnatal week [ 176 ] and BDNF deficit causes inhibition of dendritic arborization [ 92 , 177 ] and reduction of expression of genes functionally related to vesicular trafficking and synaptic communication [ 178 ].…”

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

“…In mouse Alzheimer’s disease (AD), elevated levels of H3k9me1 [51, 128] leads to the downregulation of BDNF (brain-derived neurotrophic factor). BDNF is critical for neuronal synaptic plasticity [98] as well as mediator of neuronal differentiation and cognitive functions [88]. Moreover, GRN is co-transported with BDNF within neuronal axon and dendrites [92].…”

Kinin B2 Receptor Activation Prevents the Evolution of Alzheimer’s Disease Pathological Characteristics in a Transgenic Mouse Model

“…Of note, the role of chronic BDNF exposure was observed in glutamatergic neurons in organotypic hippocampal culture. Rauti et al treated hippocampal slices with BDNF (250 ng/mL) for 72 h and observed increases in spine density and synapse number in pyramidal neurons in the hippocampus [ 41 ]. Furthermore, BDNF intracellular overexpression in hippocampal neurons increases both the frequency and the amplitude of the excitatory synapses, therefore indicating the relevance of BDNF [ 41 ].…”

“…Rauti et al treated hippocampal slices with BDNF (250 ng/mL) for 72 h and observed increases in spine density and synapse number in pyramidal neurons in the hippocampus [ 41 ]. Furthermore, BDNF intracellular overexpression in hippocampal neurons increases both the frequency and the amplitude of the excitatory synapses, therefore indicating the relevance of BDNF [ 41 ]. Therefore, in the present study, we demonstrated that the activation of BKB2R by the specific agonists NG291 and BK can become an important tool in the fight against Alzheimer’s disease.…”