Overexcitation of brain’s networks induces compensatory inhibitory mechanisms that could constrain the agility of excitatory circuits.
The protein amyloid-beta (A-beta) triggers abnormal overexcitation of brain networks responsible for learning and memory causing the brain to compensate, which may lead to the impairment of neurological functions seen in Alzheimer’s disease (AD), report researchers at the Gladstone Institute of Neurological Disease and Baylor College of Medicine.
“Such abnormal network activity in Alzheimer’s patients was thought to be a collateral or secondary event caused by the degeneration of nerve cells,” points out Jorge J Palop, Ph.D., Gladstone research scientist and lead author of the study. “But our study suggests that this activity may actually be a primary effect of A-beta and an early determinant of cognitive failure.”
The investigators used several genetically engineered mouse models of Alzheimer’s. They discovered that high levels of A-beta induce a type of seizure activity in learning and memory centers that is not accompanied by the usual twitching and jerking movements seen in many forms of epilepsy. In fact, it took brain wave recordings in freely behaving mice by electroencephalography and telemetry to detect the seizure activity.
Further studies of the neuronal circuitry in learning centers of the animals’ brains showed a rewiring that indicated an imbalance between the normal excitatory and inhibitory neuronal activity, the team states. The studies also indicated that the circuitry was remodeling itself to increase inhibitory circuit function.
The researchers also report finding genetic and biochemical changes in the brains of the engineered mice that indicated abnormal overexcitation of neurons as well as impaired plasticity.
The researchers wrote that their findings indicated that “cognitive deficits in (the genetically altered) mice and perhaps also in humans with AD may result from the combination of neuronal overexcitation and the subsequent development of compensatory inhibitory mechanisms that reduce overexcitation but end up constraining the functional agility of specific excitatory circuits.”
The study will be published in the September 6 issue of Neuron.
