van der Loo, R. J. | Search bioRxiv

bioRxiv2025

Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimers disease

Patients with Alzheimers disease (AD) initially show temporally-graded retrograde amnesia, which gradually progresses into more severe retrograde amnesia. Although mouse models of AD have provided insight into neurobiological mechanisms contributing to impaired formation and retrieval of new memories, the process underlying the progressive loss of remote memories in AD has remained elusive. Here, we demonstrate age-dependent remote memory decline in APP/PS1 mice, which coincides with progressive hyperexcitability of parvalbumin (PV) interneurons in the medial prefrontal cortex (mPFC). Analysis of Fos expression showed that the remote memory deficit is not mirrored by changes in reactivation of memory-encoding neurons, so-called engram cells, nor PV interneuron (re)activation, in the mPFC. However, inhibitory input is enhanced onto engram cells compared to non-engram cells specifically in APP/PS1 mice. Our data indicate that age-dependent remote memory impairment in APP/PS1 mice is due to increased innervation of cortical engram cells by hyperexcitable PV interneurons, suggesting that dysfunctional inhibitory microcircuits in the neocortex mediate progressive retrograde amnesia in AD.

neuroscience↗

bioRxiv2018

Gpr158 deficiency impacts hippocampal CA1 neuronal excitability, dendritic architecture, and affects spatial learning

G-protein-coupled receptor 158 (Gpr158) is highly expressed in striatum, hippocampus and prefrontal cortex. It gained attention as it was implicated in physiological responses to stress and depression. Recently, Gpr158 has been shown to act as a pathway-specific synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure, and function. Although rodent Gpr158 expression is highest in CA3, considerable expression occurs in CA1 especially after the first postnatal month. Here, we combined hippocampal-dependent behavioral paradigms with subsequent electrophysiological and morphological analyses from the same group of mice to assess the effects of Gpr158 deficiency on CA1 physiology and function. We demonstrate deficits in spatial memory acquisition and retrieval in the Morris water maze paradigm, along with deficits in the acquisition of extinction memory in the passive avoidance test in Gpr158 KO mice. Electrophysiological recordings from CA1 pyramidal neurons revealed normal basal excitatory and inhibitory synaptic transmission, however, Schaffer collateral stimulation yielded dramatically reduced post-synaptic currents. Interestingly, intrinsic excitability of CA1 pyramidals was found increased, potentially acting as a compensatory mechanism to the reductions in Schaffer collateral-mediated drive. Both ex vivo and in vitro, neurons deficient for Gpr158 exhibited robust reductions in dendritic architecture and complexity, i.e., reduced length, surface, bifurcations, and branching. This effect was localized in the apical but not basal compartment of adult CA1 pyramidals, indicative of pathway-specific alterations. A significant positive correlation between spatial memory acquisition and extent of complexity of CA1 pyramidals was found. Taken together, we provide first evidence of significant disruptions in hippocampal CA1 neuronal dendritic architecture and physiology, driven by Gpr158 deficiency. Importantly, the hippocampal neuronal morphology deficits appear to support the impairments in spatial memory acquisition observed in Gpr158 KO mice.

neuroscience↗