Jan-Feb-Mar 2013 Volume 14, Issue 1 Targeting Trends Reporting the latest news in Molecular Surgery Role of cholinergic neurons in the nucleus accumbens and their involvement in schizophrenic pathology Contributed by François LaPlante. Dept of Psychiatry, McGill University, Montréal, QC, Canada A post-mortem reduction in the density of targeting choline acetyltransferase (anti-ChAT- cholinergic interneurons in the ventral striatum SAP; Cat. #IT-42), microinjected bilaterally or nucleus accumbens (N.Acc.) has been (250-ng/side) into the N.Acc. of adult Sprague- Inside this issue: reported in schizophrenic brains.1,2 In this Dawley rats. We found a localized and selective Targeting Topics region the cholinergic interneurons interact 40-50% loss of cholinergic interneurons Scientific References 3 anatomically and functionally with the (minimum two weeks post-lesion) with sparing dopaminergic nerve terminals notably to of adjacent areas.3 Similarly, the toxin infusion Targeting Talk dampen the effects of excessive dopamine resulted in a 34% reduced tissue level of Spring Brain Conference 5 activity. We hypothesized that the lower level acetylcholine in the N.Acc. Targeting Tools of cholinergic neurons and subsequently the We have previously shown that partial Featured Products 7 acetylcholine release in the N.Acc may be depletion of cholinergic neurons resulted in relevant to the enhanced (ventral) striatal heightened behavioral sensitivity to Targeting Teaser dopaminergic neurotransmission, well- amphetamine and impaired sensorimotor Word Quiz 8 described in schizophrenia, and may contribute function3 analogous to those seen in to the emergence of schizophrenic symptoms. schizophrenia. Recently we observed that such The purpose of our work is to reproduce in lesions also significantly impaired performance rats the selective reduction of cholinergic in a T-maze task, a measurement of working Newsletter interneurons in the N.Acc. and study the memory. In addition, in vivo activation of Highlights physiological and behavioral consequences of dopamine release in the prefrontal cortex was such lesions with relevance to schizophrenia. markedly reduced; this deficit correlated ◆ SfN 2012 Poster Winners We employed the saporin immunotoxin (continued on page 6) (page 2) ◆ Spring Brain Conference Representative sections of March 20-23, 2013 ChAT-immunostained tissues (page 5) of N.Acc. from rats that (A and C) received an intra- ◆ Teaser Winners accumbens micro-injection of (page 6) rabbit IgG-SAP (Cat. #IT-35; 250 ng) as control group, and ◆ anti-ChAT-SAP (B and D) received an intra- (page 7) accumbens micro-injection anti-ChAT-SAP (250 ng). The administration of anti-ChAT- SAP reduced significantly the Denise Higgins, Editor amount of cholinergic interneurons at the injection site and spared the adjacent areas like the dorsal striatum. Scales A and B = 200 µm; C and D = 1 mm; ac: anterior commissure. Targeting Trends, Page 2 Volume 14, Issue 1 Society for Neuroscience Poster of the Year Winner The Poster of the Year winner was Ko Zushida of Rutgers University who presented his poster “The GRP peptide and the GRPR-positive interneurons control fear acquisition and extinction” by K. Zushida, K. Light, S. Uchida, C. Hevi and G.P. Shumyatsky. This work involved the removal of GRPr- expressing inhibitory interneurons with Bombesin-SAP. Bombesin is the frog-skin analog of gastrin-releasing peptide. The result was enhancement of aspects of fear memory. The importance of fear acquisition and extinction has become a topic of major importance and these authors have found a nice tool for its examination. featuring Bombesin-SAP (Cat. #IT-40) Doug Lappi congratulates Ko Zushida on the winning ATS Poster of the Year. The Society for Neuroscience Meeting was a wonderful opportunity to meet scientists and see the research they’ve accomplished with our products. Each year, ATS chooses an Poster of the Year that is the culmination of a great idea, demonstrates targeted specificity and displays fantastic data. Congratulations this year to Ko Zushida and his colleagues. ATS is already looking forward to next year. We hope to see you in San Diego, November 9-13, 2013. Honorable Mention went to Dr. Chantal Mathis who presented her poster “Combined loss of entorhinal and basal forebrain cholinergic hippocampal inputs deeply impairs Honorable Mention went to Santosh Mishra who spatial navigation memory in C57BL/6J and hAPPxapoE presented his excellent poster from S.K. Mishra, S. Holzman mice” authored by C. Mathis, P.-H. Moreau, C. Zerbinatt, R. and M.A. Hoon: “Neuromedin B serves a role in nociceptive Goutagny, B. Cosquer, K. Geiger, C. Kelche and J.C. Cassel. signaling.” They used NMB-SAP to specifically eliminate This poster showed, among many things, that human ApoE4 NMB receptor-expressing superficial dorsal horn interneurons knocked-in mice treated with mu p75-SAP to eliminate and determined that they are required for responses to noxious cholinergic hippocampal neurons had greater learning deficits heat, but not for reactions to mechanical and pruritic stimuli, than ApoE3-knocked-in mice, consistent with the role of indicating a role for these neurons in perception of thermal ApoE4 as a genetic risk factor for Alzheimer’s Disease. stimuli. featuring mu p75-SAP (Cat. #IT-16) featuring NMB-SAP (custom conjugate) Volume 14, Issue 1 Targeting Trends, Page 3 Targeting Topics: Recent Scientific References Reviewed by Matthew Kohls Histamine release in the basal 2.5 µg of conjugate. The results indicate Role for kisspeptin/neurokinin forebrain mediates cortical activation that loss of cortical acetylcholine B/dynorphin (KNDy) neurons in through cholinergic neurons. function will interfere with adaptation to cutaneous vasodilatation and the Zant JC, Rozov S, Wigren HK, Panula P, memory impairments caused by estrogen modulation of body Porkka-Heiskanen T. structural damage in episodic memory temperature. J Neurosci 32(38):13244-13254, 2012. centers. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, McMullen NT, Rance NE. The basal forebrain modulates many Form and function of the M4 cell, an Proc Natl Acad Sci U S A 109(48):19846- functions, among them the regulation of intrinsically photosensitive retinal 19851, 2012. wakefulness and cortical arousal. ganglion cell type contributing to Previous data has linked increases in geniculocortical vision. Menopause is marked by estrogen histaminergic transmission to increases Estevez ME, Fogerson PM, Ilardi MC, withdrawal, and also by hot flushes. in wakefulness. In order to further Borghuis BG, Chan E, Weng S, Auferkorte Given the fact that hypothalamic levels investigate various facets of this system, ON, Demb JB, Berson DM. of kisspeptin/neurokinin B/dynorphin the authors injected 230 ng of 192-IgG- J Neurosci 32(39):13608-13620, 2012. (KNDy) neurons are significantly altered SAP (Cat. #IT-01) into the horizontal in menopause, the authors investigated diagonal band of Broca/substantia Intrinsically photosensitive retinal whether these neurons are involved in innominata/magnocellular preoptic area ganglion cells (ipRGCs) are cells that the generation of flushes. Rats received of rats. While control animals displayed contain the photopigment melanopsin. In bilateral injections of NK3-SAP (Cat. several changes on administration of this work the authors extensively #IT-63) into the arcuate nucleus – a total exogenous histamine, the lesioned characterize the M4 ipRGCs. A of 40 ng. Blank-SAP (Cat. #IT-21) was animals had none of these changes. melanopsin antibody (Cat. #AB-N38) at used as control. The data indicate that a 1:10,000 dilution was used to KNDy neurons promote cutaneous determine the presence of melanopsin by vasodilation, and play a role in 17β- immunohistochemistry. estradiol modulation of body Diffusion-weighted magnetic temperature, supporting the hypothesis resonance imaging detection of basal that these neurons could play a role in forebrain cholinergic degeneration in the generation of hot flushes. a mouse model. CD22 Antigen Is Broadly Expressed Kerbler GM, Hamlin AS, Pannek K, on Lung Cancer Cells and Is a Target Kurniawan ND, Keller MD, Rose SE, for Antibody-Based Therapy. Coulson EJ. Neuroimage 66C:133-141, 2012. Tuscano JM, Kato J, Pearson D, Xiong C, Newell L, Ma Y, Gandara DR, O’Donnell RT. The authors examined the effectiveness Cancer Res 72(21):5556-5565, 2012. of diffusion MRI using diffusion tensor The median overall survival of patients imaging (DTI) and probabilistic tractography in detecting cholinergic loss with advanced, unresectable, non-small Acetylcholine facilitates recovery of in a mouse model. Mice received cell lung cancer is 9-12 mos. A potential episodic memory after brain damage. therapeutic target is CD22, a protein bilateral 0.2-µg icv injections of mu p75- Croxson PL, Browning PG, Gaffan D, Baxter MG. SAP (Cat. #IT-16). Rabbit IgG-SAP expressed on lung cancer cells. The J Neurosci 32(40):13787-13795, 2012. authors examined the use of the (Cat. #IT-35) was used as control. The animals were then examined using DTI. monoclonal antibody HB22.7 as an Episodic memory is controlled by The data indicate that DTI is a valid antitumor agent. To assess several interconnected brain structures. technique for assessment of cholinergic internalization of the antibody, it was The order in which these structures loss in septo-hippocampal tracts as a first incubated with 10 µg/ml Mab-ZAP sustain damage can affect the processes result of Alzheimer’s disease. (Cat. #IT-04) then applied to two lost. In this work the authors performed different cancer cell lines in culture. numerous bilateral injections of ME20.4- (continued on page 4) Analysis of cell viability demonstrated SAP (Cat. #IT-15) into the infero- that CD22 internalized when bound by temporal cortex, the medial surface of Don’t see your publication here? the antibody-toxin complex, suggesting the temporal lobe, the perirhinal and Send us a PDF at [email protected] that targeting CD22 has therapeutic entorhinal cortex, and the temporal pole and we’ll be sure to review it in the potential. of monkeys.