Functional Eviction of Aging Neurons via Perineuronal Net–Mediated Metabolic Silencing

The aging brain does not simply lose neurons; it actively silences metabolically inefficient cells by enclosing them in reinforced perineuronal nets (PNNs) that dampen excitability and suppress autophagy, preserving viability while removing them from functional circuits. This hypothesis extends the observation that microglia prune weak synapses [1] and that reduced neuronal activity correlates with longevity [2], proposing a neuron‑intrinsic switch from synaptic pruning to network eviction when energy budgets fall.

Mechanistic core

• Low‑activity neurons increase secretion of TGF‑β1, which drives upregulation of chondroitin sulfate proteoglycans (aggrecan, brevican) in the extracellular matrix, forming dense PNNs that impede ion channel diffusion and raise the threshold for action potential generation.
• Concurrently, TGF‑β1 signaling inhibits AMPK activation, leading to reduced mTORC1 activity and a blockade of macroautophagic flux [4]. The resulting accumulation of damaged mitochondria is tolerated because apoptotic pathways remain suppressed by elevated BCL‑2 expression, a state we term 'metabolic hibernation'.
• Microglia continue to prune synapses via elevated C1q/CD47 imbalance [1], but the neuronal soma remains intact, explaining why cell body counts persist despite loss of synaptic inputs [3].

Testable predictions

1. In aged mouse cortex, layers II/III neurons with low baseline calcium imaging signals will show significantly higher PNN marker intensity (aggrecan immunostaining) and lower LC3‑II puncta compared with high‑activity neighbors.
2. Acute enzymatic degradation of PNNs using chondroitinase ABC will restore spontaneous firing rates in these low‑activity neurons without increasing cleaved caspase‑3 positivity, indicating reversible silencing.
3. Behavioral rescue: aged mice treated with chondroitinase ABC in the prefrontal cortex will exhibit improved performance on working‑memory tasks, correlating with restored neuronal activity rather than new neurogenesis.
4. Conversely, genetically overexpressing TGF‑β1 in young excitatory neurons will induce PNN formation, reduce autophagic flux, and impair cognition, mimicking aged phenotypes.

Falsifiability If PNN removal fails to reactivate silent neurons or does not improve cognition despite verified synaptic reconnection, the hypothesis that functional eviction relies on perineuronal‑net‑mediated metabolic silencing would be refuted. Likewise, evidence of widespread neuronal death accompanying PNN degradation would contradict the claim that neurons remain viable in a hibernated state.

This framework repositions age‑related cognitive decline as a reversible network‑level adaptation to energetic constraint, suggesting that therapeutic strategies targeting extracellular matrix rigidity may restore cognitive function without needing to prevent neuronal loss.