Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions

TY - JOUR

T1 - Postnatal disruption of the disintegrin/metalloproteinase ADAM10 in brain causes epileptic seizures, learning deficits, altered spine morphology, and defective synaptic functions

AU - Prox, Johannes

AU - Bernreuther, Christian

AU - Altmeppen, Hermann

AU - Grendel, Jasper

AU - Glatzel, Markus

AU - D'Hooge, Rudi

AU - Stroobants, Stijn

AU - Ahmed, Tariq

AU - Balschun, Detlef

AU - Willem, Michael

AU - Lammich, Sven

AU - Isbrandt, Dirk

AU - Schweizer, Michaela

AU - Horré, Katrien

AU - De Strooper, Bart

AU - Saftig, Paul

PY - 2013/8/7

Y1 - 2013/8/7

N2 - The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with α-secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid β (Aβ) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPα and increased levels of sAPPβ and endogenous Aβ peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.

AB - The metalloproteinase ADAM10 is of importance for Notch-dependent cortical brain development. The protease is tightly linked with α-secretase activity toward the amyloid precursor protein (APP) substrate. Increasing ADAM10 activity is suggested as a therapy to prevent the production of the neurotoxic amyloid β (Aβ) peptide in Alzheimer's disease. To investigate the function of ADAM10 in postnatal brain, we generated Adam10 conditional knock-out (A10cKO) mice using a CaMKIIα-Cre deleter strain. The lack of ADAM10 protein expression was evident in the brain cortex leading to a reduced generation of sAPPα and increased levels of sAPPβ and endogenous Aβ peptides. The A10cKO mice are characterized by weight loss and increased mortality after weaning associated with seizures. Behavioral comparison of adult mice revealed that the loss of ADAM10 in the A10cKO mice resulted in decreased neuromotor abilities and reduced learning performance, which were associated with altered in vivo network activities in the hippocampal CA1 region and impaired synaptic function. Histological and ultrastructural analysis of ADAM10-depleted brain revealed astrogliosis, microglia activation, and impaired number and altered morphology of postsynaptic spine structures. A defect in spine morphology was further supported by a reduction of the expression of NMDA receptors subunit 2A and 2B. The reduced shedding of essential postsynaptic cell adhesion proteins such as N-Cadherin, Nectin-1, and APP may explain the postsynaptic defects and the impaired learning, altered network activity, and synaptic plasticity of the A10cKO mice. Our study reveals that ADAM10 is instrumental for synaptic and neuronal network function in the adult murine brain.

KW - ADAM Proteins

KW - Amyloid Precursor Protein Secretases

KW - Amyloid beta-Protein Precursor

KW - Animals

KW - Animals, Newborn

KW - Brain

KW - Cadherins

KW - Calcium-Calmodulin-Dependent Protein Kinase Type 2

KW - Cell Adhesion Molecules

KW - Dendritic Spines

KW - Disease Models, Animal

KW - Epilepsy

KW - Gene Expression Regulation, Developmental

KW - Gliosis

KW - Learning Disorders

KW - Membrane Proteins

KW - Mice

KW - Mice, Transgenic

KW - Receptors, N-Methyl-D-Aspartate

KW - Synapses

U2 - 10.1523/JNEUROSCI.5910-12.2013

DO - 10.1523/JNEUROSCI.5910-12.2013

M3 - SCORING: Journal article

C2 - 23926248

VL - 33

SP - 12915-28, 12928a

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 32

ER -