title: Delta frequency optogenetic stimulation of the thalamic nucleus reuniens is sufficient to produce working memory deficits: relevance to schizophrenia.
abstract: BACKGROUND
  Low-frequency (delta/theta) oscillations in the thalamocortical system are elevated in schizophrenia during wakefulness and are also induced in the N-methyl-D-asparate receptor hypofunction rat model. To determine whether abnormal delta oscillations might produce functional deficits, we used optogenetic methods in awake rats. We illuminated channelrhodopsin-2 in the thalamic nucleus reuniens (RE) at delta frequency and measured the effect on working memory (WM) performance (the RE is involved in WM, a process affected in schizophrenia [SZ]).
  
  
  METHODS
  We injected RE with adeno-associated virus to transduce cells with channelrhodopsin-2. An optical fiber was implanted just dorsal to the hippocampus in order to illuminate RE axon terminals.
  
  
  RESULTS
  During optogenetic delta frequency stimulation, rats displayed a strong WM deficit. On the following day, performance was normal if illumination was omitted.
  
  
  CONCLUSIONS
  The optogenetic experiments show that delta frequency stimulation of a thalamic nucleus is sufficient to produce deficits in WM. This result supports the hypothesis that delta frequency bursting in particular thalamic nuclei has a causal role in producing WM deficits in SZ. The action potentials in these bursts may "jam" communication through the thalamus, thereby interfering with behaviors dependent on WM. Studies in thalamic slices using the N-methyl-D-asparate receptor hypofunction model show that delta frequency bursting is dependent on T-type Ca(2+) channels, a result that we confirmed here in vivo. These channels, which are strongly implicated in SZ by genome-wide association studies, may thus be a therapeutic target for treatment of SZ.
authors.affiliation: Brandeis University, Waltham, Massachusetts.
authors.forename: Aranda R
authors.initials: AR
authors.lastname: Duan
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Carmen
authors.initials: C
authors.lastname: Varela
authors.affiliation: Brandeis University, Waltham, Massachusetts.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Brandeis University, Waltham, Massachusetts; The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Lealia
authors.initials: L
authors.lastname: Xiong
authors.affiliation: The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: Brandeis University, Waltham, Massachusetts. Electronic address: lisman@brandeis.edu.
authors.forename: John
authors.initials: J
authors.lastname: Lisman
mesh_terms: D000818:Animals; D003700:Delta Rhythm / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000209:etiology / Q000503:physiopathology*; D008570:Memory, Short-Term / Q000502:physiology*; D020644:Midline Thalamic Nuclei / Q000502:physiology*; D062308:Optogenetics; D051381:Rats; D020318:Rats, Long-Evans; D012559:Schizophrenia / Q000209:etiology / Q000503:physiopathology*; D012565:Schizophrenic Psychology
keywords: Channelrhodopsin; Delta; Optogenetics; Reuniens; Schizophrenia; Thalamus