Optogenetic and chemogenetic dissection of the causal role of ventral hippocampal hyperactivity for schizophrenia-related deficits

• Applicant: Professor Dr. Dennis Kätzel
• Subject Area: Biological Psychiatry
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388492565

• Final Report Year: 2023

Final Report Abstract

Schizophrenia is a severely debilitating psychiatric disorder, with limited treatment options - especially for the cognitive and negative symptoms of the disease, such as deficits in shortterm (or “working”) memory, attention, social interaction, and motivation. Several studies in humans have suggested that an early and anatomically spreading hyperactivity in a certain brain region, the anterior hippocampus, represents one of the most reliably detected neural aberrations in patients before and during the onset of psychotic symptoms, which constitute the defining diagnostic criterion for this disease. However, although few studies have revealed correlations between such hippocampal hyperactivity and symptoms, it remained unclear to what extent this pathological activity is actually causal for such symptoms. This question is important because it would imply that a reduction of this hyperactivity, at best already before the first psychotic episode – i.e. in the so-called prodromal phase of schizophrenia – could halt disease progression, including later hippocampal atrophy, presenting an effective early intervention. Using experiments in mice, our DFG-funded project (KA 4594/2-1) aimed to clarify, if this hippocampal hyperactivity is actually causal for rodent correlates of schizophrenia symptoms and, if so, (1) what are the effects of a hyperactivity in two distinct subregions of the hippocampus (called CA1 and subiculum), (2) if the mechanism entails the reduction of the communication between the hippocampus and the prefrontal cortex (a region also impacted in schizophrenia), specifically due to a reduction of a specific type of synaptic receptor, the NMDA glutamate receptor (NMDAR), in prefrontal pyramidal neurons, and (3) if the reduction of hyperactivity already present in a specific mouse model of (the prodromal phase of) this disease, the cyclin-D2 knockout (CD2-KO) mouse, can improve its schizophrenia-related deficits. We have found that, in contrast to expectation, the experimentally induced hyperactivity of the CA1 area – rather than of the subiculum - causes several correlates of cognitive symptoms, and therefore could account for the presence of such symptoms already in the prodromal state (question (1)). Regarding question (2), we found that our original hypothesis (see above) was incorrect: for example, a hypofunction of NMDARs in prefrontal cortex did not cause a wide range of schizophrenia-related symptoms, but a rather specific working memory deficit. The pursuit of question (3) did not yield meaningful results. However, we did discover a therapeutic effect of an indirect strengthening of inhibition in the hippocampus through application of the re-purposable compound N-acetyl-cysteine (NAC) in the same CD2-KO model. These results strengthen the notion that a reduction of activity in the CA1 region could be clinically effective and suggest NAC-application as one possible therapy.

Publications

• Can N-Methyl-D-Aspartate Receptor Hypofunction in Schizophrenia Be Localized to an Individual Cell Type?. Frontiers in Psychiatry, 10.
  Bygrave, Alexei M.; Kilonzo, Kasyoka; Kullmann, Dimitri M.; Bannerman, David M. & Kätzel, Dennis
  
• Hippocampal Hyperactivity as a Druggable Circuit-Level Origin of Aberrant Salience in Schizophrenia. Frontiers in Pharmacology, 11.
  Kätzel, Dennis; Wolff, Amy R.; Bygrave, Alexei M. & Bannerman, David M.
  
• A low-cost open-source 5-choice operant box system optimized for electrophysiology and optophysiology in mice. Scientific Reports, 11(1).
  Kapanaiah, Sampath K. T.; van der Veen, Bastiaan; Strahnen, Daniel; Akam, Thomas & Kätzel, Dennis
  
• Delayed-matching-to-position working memory in mice relies on NMDA-receptors in prefrontal pyramidal cells. Scientific Reports, 11(1).
  Kilonzo, Kasyoka; van der Veen, Bastiaan; Teutsch, Jasper; Schulz, Stefanie; Kapanaiah, Sampath K. T.; Liss, Birgit & Kätzel, Dennis
  
• Highly task-specific and distributed neural connectivity in working memory revealed by single-trial decoding in mice and humans. Cold Spring Harbor Laboratory.
  Strahnen, Daniel; Kapanaiah, Sampath K.T.; Bygrave, Alexei M.; Liss, Birgit; Bannerman, David M.; Akam, Thomas; Grewe, Benjamin F.; Johnson, Elizabeth L. & Kätzel, Dennis
  
• Lack of redundancy between electrophysiological measures of long-range neuronal communication. BMC Biology, 19(1).
  Strahnen, Daniel; Kapanaiah, Sampath K. T.; Bygrave, Alexei M. & Kätzel, Dennis
  
• Chronic N-acetylcysteine treatment improves anhedonia and cognition in a mouse model of the schizophrenia prodrome. Frontiers in Behavioral Neuroscience, 16.
  Bühner, Lukas Marius; Kapanaiah, Sampath K. T. & Kätzel, Dennis
  
• Distinct contributions of GluA1-containing AMPA receptors of different hippocampal subfields to salience processing, memory and impulse control. Translational Psychiatry, 12(1).
  Kilonzo, Kasyoka; Strahnen, Daniel; Prex, Vivien; Gems, John; van der Veen, Bastiaan; Kapanaiah, Sampath K. T.; Murthy, Bhargavi K. B.; Schulz, Stefanie; Sprengel, Rolf; Bannerman, David & Kätzel, Dennis
  
• Open-source, Python-based, hardware and software for controlling behavioural neuroscience experiments. eLife, 11.
  Akam, Thomas; Lustig, Andy; Rowland, James M.; Kapanaiah, Sampath KT; Esteve-Agraz, Joan; Panniello, Mariangela; Márquez, Cristina; Kohl, Michael M.; Kätzel, Dennis; Costa, Rui M. & Walton, Mark E.
  
• Open-MAC: A low-cost open-source motorized commutator for electro- and opto-physiological recordings in freely moving rodents. HardwareX, 14, e00429.
  Kapanaiah, Sampath K.T. & Kätzel, Dennis