11 - 11. Neurotrophins

11. Neurotrophins

© SPMM Course 9. Glycine  Glycine is the primary inhibitory neurotransmitter in the spinal cord  It has the simplest structure of all aminoacids  It is synthesized primarily from serine by serine trans-hydroxymethylase and glycerate dehydrogenase, both of which are rate-limiting steps.  Glycine acts as a ‘mandatory adjunctive neurotransmitter’ for glutamate receptors; the excitatory glycine site on the NMDA receptor is called non-strychnine-sensitive glycine receptor.  Strychnine-sensitive glycine receptor is an inhibitory receptor seen in the spinal cord where glycine acts independently.  Facilitating glycine transmission can help reduce negative symptoms of schizophrenia. An experimental agent called bitopertin is a glycine reuptake inhibitor that has shown some early promise in reducing negative symptoms.

10. Endocannabinoids  Two endogenous cannabinoid substances

Anandamide (a weak ligand) and 2arachnidonylglycerol (a strong ligand) are formed from arachidonic acid and ethanolamine.  The two types of cannabinoid receptors, central (CB1) and peripheral (CB2), both bind tetrahydrocannabinol (THC), the active ingredient of marijuana.  Anandamide lowers intraocular pressure, decreases activity level, and relieves pain.

11. Neurotrophins These are substances that act as polypeptide growth factors influencing proliferation and differentiation of neurons and glial cells. The best-characterised factors are Nerve growth factor (NGF); brain derived neurotrophic factor (BDNF), neurotrophin 3 and neurotrophin 4. According to neurotrophin hypothesis neurons compete during development for the limited resource of growth factors in the target region. Those neurons that are highly responsive, e.g. via high affinity binding sites, survive while others undergo programmed cell death. Incorrect targeting of axons may also lead to apoptosis (programmed cell death). BDNF may have a role in long-term potentiation (LTP) of memory. In animals, chronic stress leads to down regulation of BDNF. BDNF has been shown to have trophic effects on serotonergic and noradrenergic neurons. SSRIs and other antidepressants including ECT up regulate BDNF. The time course of this up regulation coincides with observed therapeutic actions of antidepressant interventions. A single nucleotide polymorphism in the BDNF gene on chromosome 11p13 results in an amino-acid substitution of valine (val) with methionine (met) at codon 66 (Val66Met) reducing BDNF activity. BDNF met/met mice demonstrate increased anxiety. Clinical studies in humans have demonstrated that subjects with the Val66Met allele have impaired hippocampal activation and performance. It is controversial if BDNF polymorphism increases the risk of clinical disorders or not.