Science I Early treatment of newborns may delay the onset of Huntington's disease

Author I A fish

Huntington's disease (HD) is a neurodegenerative disease in which patients develop motor, cognitive, and psychiatric disorders, symptoms usually first appear between the ages of thirty and fifty, the time from the onset of the disease to death is usually ten to thirty years, and there is still no effective treatment
for HD.

Huntingtin protein (HTT) is a scaffold protein involved in intracellular material transport, the mutated form of HTT causes HD, and HTT is also involved in neurodevelopmental processes [1
].
Because HD is a late-onset disease, embryonic developmental defects observed in HD-mode mice are often considered disease-independent
.
However, many neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, have clues in the early stages of development [2
].
So, does HD also have a developmental window during which neurodevelopmental abnormalities make patients more susceptible to disease?
Recently, the research team of Sandrine Humbert from the Grenoble Institute of Neuroscience in France published an article in Science titled Treating early postnatal circuit defect delays Huntington' disease onset and pathology in mice, found that in the first week after birth, HD-mode mice have lower excitatory synaptic activity in layers 2/3 of the cortex, low glutamate receptor expression, and exhibit sensorimotor deficits, but at the second week, these defects can be self-repaired and returned to normal levels
.
Enhancing glutamatergic synaptic transmission with drugs in the neonatal period can salvage these neurological deficits and improve sensorimotor and cognitive function
in adult HD-mode mice.


Previous research by Sandrine Humbert's team found that HD-mode mice develop cortical precursor cell division, neuromigration, dendritic maturation, and axonal growth defects
very early [3–5], which they suspect may be due to changes in synaptic signaling and neural excitability.

So they first detected the spontaneous excitatory postsynaptic current (sEPSC) and the tiny excitatory postsynaptic current (mEPSC) of excitatory glutamatergic neurons in the cortex of HD-mode mice, and found that the frequency of sEPSC and mEPSC and the amplitude of mEPSC in HD-mode mice were lower on days 1 to 3 (P1-P3) after birth, and on days 7-10, compared with wild-type.
The frequencies of mEPSC and sEPSC in HD mode mice returned to normal, but the amplitude was higher, and by days 21-26, both frequency and amplitude returned to normal
.

AMPA glutamate receptors mediate rapid excitatory synaptic signaling, and they found that HD-mode mice had decreased expression of the AMPA receptor subunit GluA1 on day 2 and returned to normal
on day 8.

Next, they examined the excitability of layer 2/3 of the cortex and found that on days 1-3, only 30% of neurons can produce an action potential when an electric current is injected, this proportion gradually increases with age, but as neurons mature, they become less excited, and the base strength (the minimum current required to cause an action potential) gradually increases
with age.
On days 4-6, HD-mode mice were more excitated by neurons, manifested by higher peak responses and lower basis intensity, while returning to normal
by days 21-26.
As a result, newborn HD-mode mouse neurons experience transient neural circuit physiological changes that may subsequently return to normal levels
through compensatory effects.

The HD-mode mice used in this study are gene-knock-in mice (Hdh^Q7/Q111), carrying a copy of wild-type HTT and a mutated form of HTT, and it is generally believed that HD is due to the mutated form of HTT causing the functional acquisition mutation, but the researchers found that knockout of wild-type HTT also leads to a phenotype similar to HD, and in HD-mode mice, The presence of a wild-type HTT copy is necessary for the recovery of its early neurological deficits
.

Since glutamatergic synaptic transmission is involved in the dendritic maturation process, the researchers then examined the morphology of dendrites and found that in the early days, the number of first-order dendrites of HD neurons was the same as that of the wild type, but the dendrites were shorter and simpler, and by day 21, there was no difference between them and the wild type, indicating that the neuronal dendritic maturity process of HD mode mice was delayed
.

Next, to investigate whether enhanced glutamatergic synaptic delivery could save the phenotype of HD mice, they used a drug, Ampakin CX516, to enhance glutamatergic synaptic transmission, by performing intrauterine electroporation at embryo 15.
5 days and subcutaneous injection of CX516 twice a day after birth, and found that dendritic maturation delays
in HD-mode mice could be saved.

To further investigate whether CX516 affects sensorimotor function in HD-mode mice, the researchers examined early huddling behavior in mice and found that HD-mode mice had a weaker ability to hold clumps, while CX516 treatment could save HD-mode mice from clumping defects
.
In addition, the correction reflex of HD mode mice also takes longer, and CX516 treatment can also salvage this defect
.
Therefore, enhanced glutamatergic synaptic transmission can save sensorimotor deficits
in HD-mode mice.

To test whether CX516 treatment affects the course of HD, the researchers injected newborn mice with CX516 subcutaneously twice a day for a total of one week, and then performed related behavioral experiments at week 5, 2 months, and 6 months, respectively, and found that early CX516 treatment could delay the emergence
of HD-related behavioral defects in adulthood 。 Histological and magnetic resonance imaging tests performed at the 8th month found that CX516 treatment could save the density of spinal cord dendrites and excitatory synapses in HD-mode mice, and the volume changes in the brain striatum, cortex and hypothalamus also recovered
.
Therefore, CX516 processing early after birth can delay the HD process
.


In general, the study found that HD-mode mice experienced a brief rise or fall in neural circuit activity after birth, subtly affecting brain structure and function, and these effects may not be manifested
until adulthood.
Their experimental results suggest that early treatment of newborns may alter the course of the disease, so this research provides an idea and theoretical basis
for developing new HD treatment strategies.

Original link: https://doi.
org/10.
1126/science.
abq5011
Publisher: Eleven

References

1.
Barnat, M.
 et al.
 Huntington’s disease alters human neurodevelopment.
 Science 369, 787–793 (2020).
2.
Stephens, M.
C.
, Brandt, V.
& Botas, J.
The developmental roots of neurodegeneration.
 Neuron 110, 1–3 (2022).
3.
Molina-Calavita, M.
 et al.
 Mutant huntingtin affects cortical progenitor cell division and development of  the mouse neocortex.
 J.
Neurosci.
 Off.
J.
Soc.
 Neurosci.
 34, 10034–10040 (2014).
4.
Barnat, M.
, Le Friec, J.
, Benstaali, C.
& Humbert, S.
Huntingtin-Mediated Multipolar-Bipolar Transition of Newborn Cortical Neurons Is  Critical for Their Postnatal Neuronal Morphology.
 Neuron 93, 99–114 (2017).
5.
Capizzi, M.
 et al.
 Developmental defects in Huntington’s disease show that axonal growth and  microtubule reorganization require NUMA1.
 Neuron 110, 36-50.
e5 (2022).
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