Parvalbumin and GAD65 interneuron inhibition in the ventral hippocampus induces distinct behavioral deficits relevant to schizophrenia.
Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ∼80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ∼40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes.
Department of Psychology and.
Robin
R
Nguyen
Department of Psychology and.
Mark D
MD
Morrissey
Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
Vivek
http://orcid.org/0000-0002-0805-827X
V
Mahadevan
Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
Janine D
JD
Cajanding
Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
Melanie A
http://orcid.org/0000-0003-2984-8630
MA
Woodin
Department of Psychology and Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
John S
JS
Yeomans
Department of Psychology and Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada.
Kaori
K
Takehara-Nishiuchi
Department of Psychology and Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada kim@psych.utoronto.ca.
Jun Chul
JC
Kim
D000200:Action Potentials; D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008124:Locomotion; D018782:Maze Learning; D051379:Mice; D009433:Neural Inhibition; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000819:agonists; D013216:Reflex, Startle; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D055366:Synaptic Potentials
D010320:Parvalbumins; D043588:Receptor, Muscarinic M4; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D003024:Clozapine; C079149:clozapine N-oxide
DREADD; GABA; parvalbumin; schizophrenia; ventral hippocampus