Hyperexcitable Parvalbumin Interneurons Render Hippocampal Circuitry Vulnerable to Amyloid Beta
Sara Hijazi,
Tim S. Heistek,
Rolinka van der Loo,
Huibert D. Mansvelder,
August B. Smit,
Ronald E. van Kesteren
Affiliations
Sara Hijazi
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands
Tim S. Heistek
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands
Rolinka van der Loo
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands
Huibert D. Mansvelder
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands
August B. Smit
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands
Ronald E. van Kesteren
Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, De Boelelaan 1085, 1081 HV Amsterdam, the Netherlands; Corresponding author
Summary: Parvalbumin (PV) interneuron dysfunction is associated with various brain disorders, including Alzheimer disease (AD). Here, we asked whether early PV neuron hyperexcitability primes the hippocampus for amyloid beta-induced functional impairment. We show that prolonged chemogenetic activation of PV neurons induces long-term hyperexcitability of these cells, disrupts synaptic transmission, and causes spatial memory deficits on the short-term. On the long-term, pyramidal cells also become hyperexcitable, and synaptic transmission and spatial memory are restored. However, under these conditions of increased excitability of both PV and pyramidal cells, a single low-dose injection of amyloid beta directly into the hippocampus significantly impairs PV neuron function, increases pyramidal neuron excitability, and reduces synaptic transmission, resulting in significant spatial memory deficits. Taken together, our data show that an initial hyperexcitable state of PV neurons renders hippocampal function vulnerable to amyloid beta and may contribute to an increased risk for developing AD.
