Effects of BDNF and NT‐4/5 on Striatonigral Neuropeptides or Nigral GABA Neurons In Vivo

Abstract

Supranigral infusions of the TrkB-receptor-preferring neurotrophins BDNF or NT-4/5 augment locomotor behaviours, pars compacta firing rates and striatal dopamine metabolism. However these actions of BDNF or NT-4/5 may involve other neurotransmitter systems in addition to dopamine neurons in the substantia nigra. We thus investigated the effects of 2-week supranigral infusions of BDNF or NT-4/5 on rat peptidergic striatonigral neurons and nigral GABAergic neurons. Radioimmunoassay revealed that BDNF and NT-4/5 elevated substantia nigra levels of substance P (by 46 and 57% respectively) and substance K (by 64 and 81%). In addition, BDNF elevated substance K by 59% in a nigral projection area, the superior colliculus. NT-4/5 elevated dynorphin A in the substantia nigra (by 52%) and met-enkephalin in substantia nigra and globus pallidus (by 89%). None of these neuropeptides were altered in the striatum. Consistent with these findings, supranigral infusions of BDNF elevated the mRNA for preprotachykinin A in striatal neurons. In the same animals, glutamic acid decarboxylase (GAD)67 mRNA was increased by 48% in the substantia nigra. The cross-sectional area of GAD67-positive neuronal somata in the BDNF-infused nigra was increased by 59%, and 70% of nigral GABAergic neurons had a cross-sectional area > 550 microns2, whereas 95% of the neurons in vehicle-infused animals had cross-sectional areas < 550 microns2. Thus, supranigral infusions of BDNF or NT-4/5 increase tachykinin mRNA and protein levels within striatonigral neurons and increase the size and GAD67 mRNA expression levels of nigral GABAergic neurons. These results suggest that BDNF or NT-4/5 may modify the output of the basal ganglia not only through effects on dopamine neurons but also by increasing neurotransmission in striatonigral peptidergic and nigral GABAergic pathways.

GDNF availability determines enteric neuron number by controlling precursor proliferation

“…Other neurotrophic factors (e.g. neurotrophin 3, brain derived neurotrophic factor, neurotrophin 4/5) are also known to modulate neurotransmitter release and synaptic function (Arenas et al, 1996;He et al, 2000;Lessmann et al, 1994;Lessmann and Heumann, 1998;Li et al, 1998;Liou and Fu, 1997;Lohof et al, 1993). The role of GDNF and NRTN in synaptic transmission within the ENS will need further investigation.…”

Amelioration of chronic neuropathic pain after partial nerve injury by adeno-associated viral (AAV) vector-mediated over-expression of BDNF in the rat spinal cord

“…BDNF has been demonstrated to directly rescue CNS GABA neurons and stimulate GABA neurotransmitter synthesis. [29][30][31][32] Exogenous BDNF has been seen to have a direct positive effect on both uninjured 33 and injured 34 serotonergic neurons in the brainstem, increasing 5HT synthesis and promoting regeneration of 5HT-axons, respectively. Transplants of BDNF-secreting cells in the subarachnoid space after nerve injury has been shown to restore the endogenous GABA system within 1 week after grafting.…”

“…4,5,[37][38][39][40] Whether such loss of GABA synthesis is due to excitotoxic cell death of GABA interneurons or temporary or permanent alterations in the neurotransmitter's synthesis, is not known, but neurotrophins such as BDNF may act directly to intervene in cell death and/or regulate GAD enzyme activity, as has been seen with BDNF and other GABA cells. [29][30][31][32] Assigning only a antinociceptive function for endogenous BDNF in neuropathy is difficult. Neurotrophic factors such as BDNF, and NT-3 play a significant role in the development, and perhaps maintenance, of the sensory neurons responsive to temperature and tactile pain, evidenced in neurotrophin-knockout mice.…”

Neurons on the Move: Migration and Lamination of Cortical Interneurons

“…However, the role of BDNF in cortical interneuron development is not without debate. Other studies have suggested that disruption of BDNF signalling leads to downregulation of CB and other neuropeptides expressed in interneurons [91,123,124]. This would cast some doubt as to whether the reduction of interneuron numbers in the absence of TrkB reflects an actual defect in migration or simply a reduction of cell markers.…”