Intellectual disability may not need to last a lifetime
Improvements in motor function and memory following brief treatment with the drug LM22A-4, suggest human neurodevelopmental disorders may be reversable even after onset of symptoms. If so, this suggests disorders with intellectual disability, including Rett Syndrome and autism, may not need to last a lifetime.
Rett syndrome is an X linked disorder affecting about one of every 10,000 females worldwide. Infants appear to develop normally for 6-18 months, before symptoms begin to appear. The disorder affects intellectual ability displaying characteristics of autism, deficits in muscle motor control and sensory perception, breathing irregularities, and epilepsy.
Most Rett syndrome individuals have a mutation in a gene called MeCP2. The MeCP2 mutation reduces a brain-derived neurotrophic factor, or BDNF. This factor missing in the brain of a female mouse leads to her exhibiting the same symptons as found in our human version of the disorder. The BDNF loop domain acts on specific neurons in our central and peripheral nervous systems. It is there to help support our existing neurons and encourage growth and differentiation in newly growing neurons and the synapses that connect them.
After learning that a small-molecule drug improves breathing in Rett syndrome mice, Lucas Pozzo-Miller PhD, professor of neurobiology in the University of Alabama (UAB) School of Medicine in Birmingham, wondered if that same drug might have beneficial effects on other aspects of Rett.
Pozzo-Miller with Frank Longo MD at Stanford University, who had shown the drug's improvement in breathing of Rett mice, and other colleagues found that a simple four-week systemic treatment of female mice carrying one mutant MeCP2 gene, were able to improve their neurologic abilities. The mice were able to notice an object had been moved in object—location memory tests.
The treatment also appears to strengthen synapses in the hippocampus — a phenomenon underlying the plasticity of brain function. Treatment increased the distance mice traveled in an open field test back to normal levels, a measure of general locomotor activity.
The researchers looked deep into brain neurobiology to find that LM22A-4 improves spatial memory in excitatory synaptic transmission or the process by which signaling molecules called neurotransmitters, release, bind to and activate receptors of another neuron in the hippocampus of the brain. The treatment raised neurotrasmission levels allowing normal synaptic plasticity with behavioral learning and improved memory.
Collaborating with Longo and with David Katz PhD, at Case Western Reserve University, increased the team's growing realization that neurodevelopmental disorders affecting the early brain may be treatable. Improvements coming even after the onset of symptoms, adds Pozzo-Mille, offering hope to many patients and their families and caregivers.
"Neurodevelopmental disorders with intellectual disability and autism may not need to last a lifetime."
Lucas Pozzo-Miller PhD, Professor, Neurobiology, University of Alabama, School of Medicine, Birmingham, Alabama, USA.
Rett mouse experiments by Longo and collaborators reveal the drug LM22A-4 also promotes motor recovery after hypoxic-ischemic strokes, improves motor impairment in Huntington's disease and enhances recovery of limb function after spinal cord injury in mice.
The work is published in the journal Disease Models and Mechanisms.
Rett syndrome (RTT) is a neurodevelopmental disorder caused by
mutations in methyl-CpG-binding protein-2 (MECP2), a transcriptional
regulator of many genes, including brain-derived neurotrophic factor
(BDNF). BDNF levels are reduced in RTT autopsy brains and in multiple
brain areas of Mecp2-deficient mice. Furthermore, experimental
interventions that increase BDNF levels improve RTT-like phenotypes
in Mecp2 mutant mice. Here, we characterized the actions of a smallmolecule
ligand of the BDNF receptor TrkB in hippocampal function in
Mecp2 mutant mice. Systemic treatment of female Mecp2 heterozygous
(HET) mice with LM22A-4 for 4 weeks improved hippocampaldependent
object location memory and restored hippocampal longterm
potentiation (LTP). Mechanistically, LM22A-4 acts to dampen
hyperactive hippocampal network activity, reduce the frequency and
amplitude of miniature excitatory postsynaptic currents (mEPSCs), and
reduce the frequency of spontaneous tetrodotoxin-resistant Ca2+ signals
in Mecp2 mutant hippocampal neurons, making them comparable to
those features observed in wild-type neurons. Together, these
observations indicate that LM22A-4 is a promising therapeutic
candidate for the treatment of hippocampal dysfunction in RTT.
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Aug 2, 2017 Fetal Timeline Maternal Timeline News News Archive
LM22A-4 improves LTP at CA3-CA1 synapses in hippocampus of female Mecp2 HET mice. The BDNF loop domain acts on certain neurons in the central and peripheral nervous system, to support survival of existing neurons and encourage growth and differentiation of new neurons and synapses.
Image credit: http://www.hippocampus.org