Inhibitory neurotransmission is important for brain function and requires specific transmitter receptors that are organized in synaptic domains. Gephyrin is a cytoskeletal organization protein that binds tubulin and plays an important role in clustering and organizing select inhibitory neurotransmitter receptors. Here, we tested if gephyrin is altered by protein accumulation stress that is common in age-related neurodegenerative disorders. For this, we used the hippocampal slice model that has been shown to exhibit chloroquine (CQN)-induced protein accumulation, microtubule destabilization, transport failure, and declines in excitatory neurotransmitter receptors and their responses. In addition to the decreases in excitatory receptor subunits and other glutamatergic markers, we found that gephyrin isoforms were reduced across the CQN treatment period. Associated with this decline in gephyrin levels was the production of three gephyrin breakdown products (GBDPs) of 30, 38, and 48 kDa. The induced effects on gephyrin were tested for evidence of recovery through enhancement of lysosomal function that is known to promote protein clearance and microtubule integrity. Using the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK), gephyrin levels were completely restored in correspondence with the recovery of excitatory glutamatergic components. In addition, GBDPs were significantly reduced after the 2-day PADK treatment, to levels that were at or below those measured in control cultures. These findings suggest that receptor-clustering mechanisms for inhibitory synapses are compromised during protein accumulation events. They also indicate that a lysosomal enhancement strategy can protect gephyrin integrity, which may be vital for the balance between inhibitory and excitatory signaling during age-related diseases.