A fundamental feature of neural circuits is the capacity for plasticity in response to experience. During the past 60 years, mounting evidence indicates that experience-dependent changes in synaptic transmission and neuronal wiring, phenomena collectively termed synaptic plasticity, underlie the cellular basis of neural computation, learning and memory. Hebbian-like plasticity, reflected by persistent changes in synaptic and intrinsic properties, is crucial for refinement of neural circuits and information storage, however, alone it is unlikely to account for the stable functioning of neural networks. Both, stability and plasticity are hallmarks of brain function that enable adaptations to unpredictable and dynamic environment, experience and learning. Coping with constantly changing environments, neural circuits need to spend a considerable amount of their available energy to maintain homeostasis and to minimize the effects of stochastic events. Destabilization of hippocampal and cortical circuits has been widely documented in neurodegenerative disorders, e.g. Alzheimer's disease (AD), the most frequent form of late-life dementia. However, the key mechanisms that underlie stability of activity patterns in central mammalian neural circuits are largely unknown. Furthermore, how disruption of these mechanisms affects the onset and the kinetics of AD-related neuronal dysfunctions remains an enigma.
In this project, we identified the key principles and molecular pathways regulating homeostasis of firing properties at the level of neuronal populations. We identified the key regulators of firing rate homeostasis: mitochondrial DHODH and IGF1R molecules. We found that these molecules regulate firing rate homeostasis via synaptic and intrinsic excitability mechanisms. Notably, DHODH inhibition suppressed aberrant pathological hippocampal activity in mouse models of intractable epilepsy and familial AD (fAD). Our results point to mitochondria as a key regulator of activity set-points, proposing a new strategy to treat brain disorders associated with hyperactivity of hippocampal circuits.
Furthermore, we studied firing rate homeostasis in the presymptomatic stage in AD mouse models. We demonstrated that before the onset of memory decline and sleep disturbances, AD model mice display no deficits in CA1 firing rate homeostasis during active wakefulness. However, homeostatic down-regulation of CA1 firing rates is disrupted during non-rapid-eye-movement (NREM) sleep and general anesthesia. fAD mutations impair downward firing rate homeostasis, resulting in pathological activity set points in response to anesthetic drug and inhibition blockade. Thus, firing rate dyshomeostasis of hippocampal circuits is masked during active wakefulness, but surfaces during low-arousal brain states, representing an early failure of the silent disease stage.
Finally, we searched for the functional significance of firing rate dyshomeostasis in the presymptomatic AD stage. We identified that epileptiform spikes emerge during low-arousal brain states in the CA1 and mPFC regions, leading to working memory disruptions. These epileptiform spikes are driven by inputs from the thalamic nucleus reuniens. Indeed, tonic deep brain stimulation (DBS) of the nucleus reuniens effectively suppresses epileptiform spikes and restores firing rate homeostasis under anesthesia, preventing further impairments in synaptic facilitation and working memory. Notably, applying DBS during the prodromal phase in young fAD mice mitigates age-dependent memory decline. The epileptiform spike rate during anesthesia in young model mice correlates with later working memory impairments. These findings highlight the midline thalamus as a central hub of functional resilience and underscore the clinical promise of DBS in conferring resilience to AD pathology by restoring circuit-level homeostasis.
These studies identified the fundamental mechanisms of stability in central neural circuits and provide a conceptual new way to boost cognitive resilience to AD by restoring activity homeostasis.
