Due to the extensive effects of Neurotrophins (NTs) in neuronal cells, neurotrophic activity is essential for the proper development and functionality of the brain circuit ^[1][50]. For instance, hippocampal and cortical brain structure development is mainly influenced by BDNF and NT-3 signaling ^[2][3][4][51,52,53]. Additionally, NGF and BDNF during early brain development allow the differentiation of stem cells into neurons and their survival ^[5][48]. In general, NTs have been associated with the differentiation of multipotential precursor cells into multipolar and bipolar neurons and oligodendrocytes ^[5][48].

The cell fate and behavior depend on the corresponding dominant form of present NTs, due to that NTs display a high affinity for Trk receptors and low affinity for p75NTR; meanwhile, the opposite phenomenon is observed for proNTs ^[3][4][52,53]. Even though these receptors interact directly and can modulate their effects on target cells, p75NTR activation usually leads to apoptosis, while Trk activation promotes cell survival ^[6][54]. Both NTs and proNTs activity help regulate the number of neurons surviving, especially in early brain circuit development, where cell survival can be disproportionate, becoming necessary for eliminating some neurons ^[7][47].

It has been described that BDNF significantly influences early brain development, promoting stem cell differentiation into neurons and their survival ^[5][48]. For instance, in striatum stem cell-derived neuron precursors, the NT loses effect in cell survival after achieving suitable differentiation ^[8][49]. This implies that BDNF stimulates neurite outgrowth in striatum neurons but does not act as a survival factor, making it insufficient to prevent death over the time ^[8][49]. Moreover, it was shown that mice with impaired production of BDNF during the early stages of brain development experience several synaptic plasticity and transmission problems due to reduced neuron survival after stem cell differentiation ^[2][51]. These complications include the impairment of long-term potentiation (LTP) and paired-pulse facilitation (PPF) and the lack of synaptic response to high-frequency stimulation (HFS) ^[2][51]. In addition, BDNF insufficiency also causes cognitive alterations in mice and humans, such as elevated aggression, anxiety and depression-like behaviors, and a lack of learning modulation ^[9][10][55,56]. Nevertheless, it has been shown that stimulating the expression of BDNF via physical exercise has a positive impact on the attention span of children with attention deficit hyperactivity disorder (ADHD) ^[11][57].

In association with BDNF, the expression of its receptor TrkB has been studied during epilepsy, resulting in observations that it influences the rearrangement of brain neuron circuitry following epileptic seizures ^[12][58]. The decrease of this BDNF receptor in neocortical brain areas has been associated with dendritic retraction, but not with cell death following epileptic convulsions ^[12][58]. On the other hand, when proBDNF binds and activates its preferred receptor, p75NTR, it has been shown to exhibit pro-apoptotic activity in BDNF target cells ^[13][59]. Additionally, BDNF significantly influences the survival of different neuron populations in hippocampal and cortical structures ^[4][14][53,60]. Therefore, abnormally elevated levels of BDNF in the hippocampus and low levels of BDNF in cortical areas have been associated with schizophrenic psychoses ^[14][60]. It has also been found that brain-injected BDNF has neuroprotective effects in the ischemic hippocampus of rats ^[14][60]. In adults, hippocampal stem cell proliferation and differentiation are regulated by BDNF expression, which is regulated by neurological activity ^[15][61]. In turn, neurological activity, along with the expression of BDNF, has been shown to modulate neural plasticity ^[15][16][61,62].

Neurogenesis has been linked to BDNF activity in hippocampal and cortical areas of the macaque monkey embryonic brain and the hippocampus of adult rats ^[17][18][5,63]. This suggests that BDNF plays a role in the proliferation of new neurons through a significant portion of animal lifecycles. BDNF has also aided retinal detachment and reattachment in cats in protecting surviving photoreceptor cells and possibly promoting regenerative responses in peripheral tissues ^[19][64].

On the other hand, NGF activity in embryonic CNS tissues has been extendedly documented since the discovery of this NT ^[20][21][23,65]. For instance, the early development of mice’s basal brain cholinergic neuron projections to the hippocampus and cortex is enhanced by NGF ^[21][65]. However, the survival of these neurons is independent of NGF exposure ^[21][65]. When basal brain cholinergic neurons are developed in the absence of NGF, they can atrophy, which has been associated with neurological disorders such as Alzheimer’s disease ^[22][23][24,66]. In addition, exogenous exposure to NGF on atrophied cholinergic neurons enhances synaptogenesis in cortical tissue ^[22][24]. This has sparked many attempts to develop effective NGF treatments for Alzheimer’s disease ^[24][25]. Other neurological disorders have been studied concerning NGF activity, such as Huntington’s disease, in which a progressive decrease of hippocampal NGF levels has been observed in different rat model ages ^[25][26]. Furthermore, intracerebral injection of this NT in rat models restored spatial working memory and enhanced hippocampal neurogenesis ^[25][26][26,67].

Synergistic and combined effects of NGF and BDNF have been documented ^[20][23]. In vitro neuronal stem cell differentiation is significantly improved by both NTs combined than NGF or BDNF alone ^[20][23]. Combined effects of subtle variations of NGF and BDNF on neuronal cell death, physiological disorders, and cognitive problems have been documented in alcohol-exposed newborns ^[27][28][68,69]. Diverse effects of this NT have been observed in experimental conditions; however, its exact role in unperturbed brain tissues remains elusive ^[21][65].

NT-3 activity has shown associative and synergistic effects with other NTs, such as BDNF, in many NT-3 target tissues ^[29][30][70,71]. Such is the case with the extension of the time window for brain plasticity by BDNF and NT-3 exposure on neonatal rat cerebellum ^[29][70]. Added effects of BDNF and NT-3 have even made the reprogramming of human dental pulp stem cells into neurogenic and gliogenic neural crest progenitors possible ^[31][72]. NT-3 has demonstrated significant influence in aiding the activity of other NTs in multiple target tissues and cells. NT-3 own activity has shown diverse effects and influence over neural circuitry and proliferation ^[32][73]. Multiple studies have demonstrated that this NT is not only required for spinal proprioceptive afferent motor neuron connections, but its overexpression has adverse effects on synaptic selectivity between sensory and motor neurons ^[32][33][73,74]. Auditory neuron neurite outgrowth is also positively affected by NT-3 signaling ^[34][75]. In contrast to previously described neural proliferative effects, NT-3 can also inhibit cortical neural precursor proliferation via the fibroblast growth factor 2 FGF2 pathway ^[35][76]. Furthermore, abnormal NT-3 levels have been associated with neurological disorders, such as autism ^[2][51]. In cortical areas, abnormally low levels of NT-3 have been related to schizophrenic psychoses ^[9][55]. The effects of NT-3 signaling are diverse and significantly dependent on the biochemical context before tissue exposure, including the presence of other NTs such as BDNF ^[29][70].

NT-4/5 has marked effects on brain neuron circuit growth and structure after a proper stem cell differentiation stage in brain development ^[12][14][58,60]. It has been associated with BDNF in significantly influencing neural plasticity, even in a differentiated tissue ^[11][57]. For instance, NT-4/5 activity enhances glutamatergic synaptic transmissions in cultured hippocampal neurons ^[14][36][60,77]. Cerebellar granule cells have been positively induced neurite outgrowth when exposed to NT-4/5 ^[37][78]. Cultured striatal neuron survival, neurite outgrowth, and biochemical differentiation have also been positively associated with NT-4/5 modulation ^[38][79]. Studies in retinal ganglion cells also found positive modulation of neurite outgrowth and cell survival by NT-4/5 together with BDNF ^[39][40][80,81]. These results suggest that NT-4/5 has significant effects on the structure of neural circuitry in multiple brains and non-brain areas ^[36][77].

Interestingly, studies have described neuro regenerative and protective effects of NT-4/5 in adult rat neural tissues ^[41][82]. For example, the exposure of the axon from the rubrospinal motor neuron to NT-4/5, along with cervical axotomy, could cause cellular regeneration and prevent cell atrophy and death ^[42][83]. In addition, neuroinflammation after germinal matrix hemorrhage in basal ganglia is attenuated by NT-4/5-Trkb signaling ^[41][82]. These effects have also been found in Parkinson’s disease research in rats, where the efficacy of embryonic nigral grafts has been enhanced by NT-4/5 specifically ^[43][84].

Finally, behavioral changes concerning the augmenting serotonin, dopamine, and GABAergic systems are modulated by NT-4/5 expression in the basal ganglia ^[44][85]. This NT shows significant effects in multiple neural tissues, including brain areas, such as the hippocampus and striatum, specifically in adult and differentiated tissues, which perdures through most animals’ lifecycles ^[42][83].

The role of NTs is relevant in a significant portion of animal life and has vast implications for developing healthy brain circuitry ^[45][86]. A common factor between most physiological effects of NTs signaling is the promotion of neuron and/or non-neuron, such as glial and epithelial cell survival ^[46][87]. However, the homeostasis of the CNS depends not only on NTs promoting cell survival and the development of the brain, but also plays an essential role in modifying the synapsis over time ^[46][87]. In the following section, the role of NTs during synaptic plasticity will be discussed.

As previously mentioned, NTs play an essential role in maintaining homeostasis in the CNS. Within this maintenance is the regulation of synaptic plasticity, which refers to the capability to strengthen or weaken the synaptic transmission of synapsis ^[47][88]. BDNF and NT-3 are the most important and studied NTs contributing to this phenomenon.

The effect of BDNF on synaptic plasticity has been recently studied since it has been identified in specific areas where synaptic plasticity occurs, such as the hippocampus, the cerebellum, and the cerebral cortex ^[48][89]. It should be noted that these studies have mainly focused on the hippocampus because it is the region of the brain where synaptic plasticity plays a critical role in learning and memory ^[49][90]. As stated above, when mature BDNF is released, proBDNF is also released, which have opposite effects by binding to their respective receptor ^[49][90]. Studies with knockout mice for the gene encoding p75NTR have shown that proBDNF can only induce the generation of Long-Term Depression (LTD) upon the binding with p75NTR ^[50][91]. Along these lines, other studies have shown a significant decrease in LTP in adult mice models by blocking the expression of BDNF in the brain ^[48][51][89,92]. Therefore, it can be said that mature BDNF binds to TrkB and promotes the generation of LTP in adult mice ^[48][51][89,92]. Interestingly, synaptic plasticity is a phenomenon that is related to aging since the plasticity is reduced as age advances, which is linked to a decrease in BDNF ^[52][93]. Nevertheless, this result could be reversed if BDNF is administered exogenously ^[52][93].

As previously seen, BDNF impacts synaptic plasticity, which has resulted in studying the role played by the TrkB receptor ^[53][94]. This receptor has been observed preferentially located in the sites where neuronal plasticity is produced, carrying out focused signaling ^[53][94]. When BDNF interacts with TrKB, different signaling pathways are activated within the neuron ^[54][95]. These pathways are characterized by activating transcription factors such as cAMP-response-element-binding Protein (CREB) and CREB-binding protein (CBP), which activate genes that encode proteins involved in the process of neuronal plasticity and cell survival ^[54][95].

As previously stated, the expression of BDNF has been associated with neurological disorders ^[55][56][3,17]. For example, in patients with Alzheimer’s Disease, it has been observed that BDNF expression decreases drastically compared to control subjects of the same age ^[57][96]. Additionally, it was found that the protein levels that form TrkB also decrease in these patients, and the CREB signaling is altered by the presence of the β-amyloid peptide, which is one of the main peptides associated with AD ^[57][58][96,97]. These results suggest that the disease, through the use of β-amyloid peptide, blocks the correct signaling of CREB, affecting the plasticity in these patients ^[57][58][96,97]. Another disease where the role of BDNF has been studied is schizophrenia, which is characterized by cognitive impairment ^[59][98]. It has been reported that patients who have schizophrenia had serum levels of BDNF significantly lower than controls ^[60][99]. Additionally, a correlation was made between serum BDNF levels and a cognitive performance test score that showed a positive association, suggesting that low BDNF expression plays a determining role in the development of the disease ^[60][99].

In contrast to BDNF, NGF has been less studied than other NTs, but not because it is less important. It has been seen that the metabolism of NGF in AD is altered, meaning that cholinergic neurons cannot have optimal growth and plasticity since they depend on this NT for complete development ^[61][100].

In a study in adult rats, NGF levels were modified and the effects of NGF on hippocampal neurons, LTP, and learning were examined ^[62][101]. It was observed that the increase in NGF produced a significant increase in markers of the formation of new neural networks ^[62][101]. On the other hand, a blockade in releasing this NT significantly reduced LTP, impairing spatial memory in rats ^[62][101]. Thanks to these results, the researchers concluded that NGF plays an essential role in regulating mechanisms related to plasticity and memory, but the mechanisms in which NGF may intervene are still being studied.

Lastly, NT-3 plays an essential role in synaptic plasticity, which is highly expressed in the dentate gyrus of the hippocampus ^[63][102]. In a study using knockout mice for the gene that codes for NT-3, it was observed that NT-3 could regulate the differentiation of neuronal cells in the dentate gyrus, being very important for neurogenesis to occur and thus contributing to plasticity synapse in this region of the hippocampus ^[63][102].

A study investigated the role of NT-3 in hippocampal plasticity and memory in mouse models ^[63][102]. They observed that a blockade of the release of NT-3 generated a deterioration in the LTP, this being observed in neuronal synapses ^[63][102]. On the other hand, NT-3 mutant mice showed deficits in spatial memory tests ^[63][102]. These results indicate that NT-3 is just as crucial as other NTs in synaptic plasticity, participating in mechanisms still being studied.

It is known that NTs have an essential role in the myelination process, which is critical for the conduction of the nerve impulse ^[64][65][66][103,104,105]. A study performed on BDNF-/- mice showed fewer oligodendrocytes and low levels of the myelin basic protein (MBP) in different brain areas of wild-type mice ^[67][106]. These data showed a direct relationship between the expression of BDNF and MBP, but it is not the only factor involved in oligodendrocytes maturation because MBP expression was not absent in the brain of BDNF-/- mice, indicating that it is produced by another pathway ^[67][68][106,107]. Indeed, it has been described that BDNF has effects on the proliferation of oligodendrocytes progenitor cells (OPCs) and promotes its differentiation through its interaction with TrkB and the subsequent signaling pathway (MAPK/PI3K), described earlier ^[69][70][108,109]. The final effect of BDNF on the oligodendrocytes is the up-regulation of MBP, which was evaluated in BDNF+/− mice that present myelination deficit in the optical nerve, brain, and spinal cord during the postnatal development ^[71][110]. In demyelinating and inflammatory diseases such as Multiple Sclerosis (MS), it has been observed that BDNF levels were elevated in brains with an inflammatory lesion, where the primary source of this NT was the immune cells ^[72][73][111,112]. Moreover, low plasma levels of BDNF were observed in MS patients compared to controls and after relapse ^[74][75][113,114]. According to these findings, BDNF has a crucial role in MS ^[76][115].

On the other hand, NGF has the opposite effects on Schwann cells and oligodendrocytes ^[77][116]. Experiments performed in cell cultures showed that NGF can promote the myelinization of dorsal ganglia roots (DGRs) neurons by Schwann cells ^[77][116]. Contrary to this, OPCs cultured onto DGRs and in the presence of NGF showed a decreased myelinization, a lower number of differentiated oligodendrocytes, and inhibition of the maturation of oligodendrocytes ^[77][116]. These effects are through the TrkA, which is present in the DGRs ^[77][116]. Meanwhile, the inhibition of the differentiation of the OPCs is through its interaction with p75NTR ^[78][117]. The neutralization of NGF can revert the impairment in myelinization, demonstrating the negative regulation of oligodendrocytes ^[79][118]. In MS patients, it has been described that NGF is elevated in cerebrospinal fluid (CSF). In lesions zones of the brain, immature and apoptotic oligodendrocytes can be found expressing high levels of p75NTR ^[80][81][119,120].

NT-3 has been shown to promote OPCs proliferation, differentiation, and survival ^[82][83][84][121,122,123]. Also, NT-3 overexpression can promote and induce oligodendrogenesis in the injured spinal cord, besides the myelinization of ingrowing axons ^[66][105]. Moreover, NT-3, together with BDNF, promotes axonal survival after spinal cord injury preventing neuronal damage and apoptosis ^[75][85][114,124]. However, concerning MS, the role of NT-3 is poorly studied.