Inhibiting Alzheimer’s disease by restoring Parvalbumin interneuron activity

The main aim of my project was to explore the role of hippocampal PV interneurons in AD-associated memory deficits and network imbalance. In Chapter 2, we uncovered that PV interneurons are hyperexcitable at an early disease stage in APP/PS1 mice. PV interneuron hyperexcitability coincided with an increase in inhibitory transmission at pyramidal neurons in the CA1 region. Importantly, restoring PV interneuron activity at an early age reinstated inhibitory transmission in the hippocampus and consequently, prevented spatial memory deficits, up to 8 weeks after the end of the treatment. We also revealed that early PV interneuron hyperexcitability is transient and is rapidly followed by PV interneuron hypoactivity and a decrease in inhibitory transmission at 6-7 months in APP/PS1 mice. In Chapter 3, we examined whether PV interneuron hyperexcitability alone can explain the observed memory deficits and network imbalance in AD. To answer this question, we used wildtype PV-Cre mice in combination with chemogenetic tools to activate PV interneurons, in the absence of soluble Ab. Prolonged chemogenetic activation of hippocampal PV interneurons induced a sustained hyperexcitable state of PV interneurons up to 8 weeks after the end of the treatment. We found that acutely after treatment cessation (1 week), mice with increased PV activity showed spatial memory deficits in the Morris water maze, accompanied by an imbalance of synaptic transmission at pyramidal neurons in the CA1. However, 8 weeks after the end of the treatment, while PV interneurons were still hyperexcitable, spatial memory was enhanced and synaptic transmission was restored. Hence, in the absence of Ab, hippocampal microcircuits succeeded at re-establishing the E/I balance and hippocampal memory was even improved. Importantly, injection of Ab into the hippocampus at a very low dose impaired PV interneuron function, increased the excitability of pyramidal neurons, disturbed synaptic transmission in the hippocampus and undeniably caused a deficit in spatial memory. This data, therefore, validates the role of PV interneuron hyperexcitability, accompanied by Ab toxicity, in AD-associated network and memory impairments. It also implies that early PV interneuron hyperexcitability could be a causal step in later PV interneuron hypofunction. However, this data also confirms that PV hyperexcitability alone can’t explain memory deficits. Therefore, in Chapter 4, we aimed to further explore the cellular adaptations that could unravel the differences between the early time point and the late time point. Our data showed that prolonged chemogenetic activation of hippocampal PV interneurons increased the percentage of perineuronal net bearing (PNN+) PV interneurons in the CA1 region of the hippocampus, validating that activating PV interneurons increases PNN density around these cells. However, the increase of PNNs around PV interneurons could not explain the associated memory alterations as it was observed at both time points. When assessing neuronal activation at memory recall using c-Fos as a cellular marker for neuronal activity, we found that the percentage of activated PV interneurons at memory recall was only increased at the time point when memory was impaired, suggesting that an aberrant increase in PV interneuron activity at recall can impair spatial memory. Taken together, our data suggest that early PV interneuron hyperexcitability, which is likely accompanied by an aberrant increase in activity of PV interneurons during learning, could be a causal step in AD-associated network and memory impairments. When PV interneuron hyperexcitability is complemented with a toxic increase in soluble Ab levels, hippocampal microcircuits fail to adapt, leading to PV interneurons hypoactivity, pyramidal neurons hyperexcitability, E/I imbalance and impairments in learning and memory. Restoring PV interneuron activity at early stages prevented AD-associated network and memory impairments in AD mice and hence, this offers promising novel entry points for early disease intervention.