Imperial College London

Prof. William Wisden F. Med. Sci.

Faculty of Natural SciencesDepartment of Life Sciences

Chair in Molecular Neuroscience



+44 (0)20 7594 9744w.wisden Website CV




401BSir Ernst Chain BuildingSouth Kensington Campus





Publication Type

199 results found

Gundlach AL, Wisden W, Morris BJ, Hunt SPet al., 1990, Localization of preprogalanin mRNA in rat brain: in situ hybridization study with a synthetic oligonucleotide probe, Neurosci Lett, Vol: 114, Pages: 241-247, ISSN: 0304-3940

Localization of preprogalanin mRNA in rat brain: in situ hybridization study with a synthetic oligonucleotide probe

Journal article

Morris BJ, Hicks AA, Wisden W, Darlison MG, Hunt SP, Barnard EAet al., 1990, Distinct regional expression of nicotinic acetylcholine receptor genes in chick brain, Brain Res Mol Brain Res, Vol: 7, Pages: 305-315, ISSN: 0169-328X

Four genes (alpha 2, alpha 3, alpha 4 and beta 2) have been reported as encoding subunits of the nicotinic acetylcholine receptor (nAChR) in chicken brain. The mRNAs transcribed from these genes have here been localised to particular regions using in situ hybridisation histochemistry. The beta 2 mRNA was clearly the most abundant transcript, being widely distributed throughout the chick brain. In the cerebellum, all four mRNA species were present, although they showed different cellular patterns of distribution. Only alpha 2 mRNA and beta 2 mRNA were found in significant amounts in the optic tectum. In the lateral spiriform nucleus, while alpha 2 mRNA, alpha 4 mRNA and beta 2 mRNA were all very abundant, the alpha 4 mRNA was localised to a subgroup of neurons containing alpha 2 mRNA and beta 2 mRNA. This represents the first evidence that individual cells may express two different nAChR alpha subunit genes in vivo. The distributions of the 4 mRNA species showed few common features. This suggests that other neuronal nAChR genes remain to be identified, and that these 4 genes are not generally expressed in the same cells to constitute a single macromolecular complex. The results therefore provide evidence for nAChR heterogeneity in the central nervous system.

Journal article

Ymer S, Draguhn A, Wisden W, Werner P, Keinanen K, Schofield PR, Sprengel R, Pritchett DB, Seeburg PHet al., 1990, Structural and functional characterization of the gamma 1 subunit of GABA-A/benzodiazepine receptors, EMBO J, Vol: 9, Pages: 3261-3267, ISSN: 0261-4189

The GABAA receptor gamma 1 subunit of human, rat and bovine origin was molecularly cloned and compared with the gamma 2 subunit in structure and function. Both gamma subunit variants share 74% sequence similarity and are prominently synthesized in often distinct areas of the central nervous system as documented by in situ hybridization. When co-expressed with alpha and beta subunits in Xenopus oocytes and mammalian cells, the gamma variants mediate the potentiation of GABA evoked currents by benzodiazepines and help generate high-affinity binding sites for these drugs. However, these sites show disparate pharmacological properties which, for receptors assembled from alpha 1, beta 1 and gamma 1 subunits, are characterized by the conspicuous loss in affinity for neutral antagonists (e.g. flumazenil) and negative modulators (e.g. DMCM). These findings reveal a pronounced effect of gamma subunit variants on GABAA/benzodiazepine receptor pharmacology.

Journal article

Sirinathsinghji DJ, Morris BJ, Wisden W, Northrop A, Hunt SP, Dunnett SBet al., 1990, Gene expression in striatal grafts-I. Cellular localization of neurotransmitter mRNAs, Neuroscience, Vol: 34, Pages: 675-686, ISSN: 0306-4522

his study utilized the technique of in situ hybridization histochemistry to identify cells expressing neurotransmitter mRNAs in embryonic striatal tissue grafts implanted into the ibotenic acid-lesioned rat neostriatum. Synthetic 32P- or 35S-labelled oligodeoxyribonucleotide probes specific for prosomatostatin, proneuropeptide Y. proenkephalin, prodynorphin and preprotachykinin mRNAs and a 32P-labelled cRNA probe specific for glutamate decarboxylase mRNA were used to study the regional and cellular changes in these mRNA levels in the normal, lesioned and grafted neostriatum. The levels of neuropeptide Y mRNA and somatostatin mRNA were substantially increased in the striatal grafts compared with the intact control striata. The levels of glutamate decarboxylase mRNA in the grafts also appeared to be slightly elevated over those in the control striata. However, the levels of proenkephalin mRNA, prodynorphin mRNA and preprotachykinin mRNA were significantly lower in the grafts. The increased levels of neuropeptide Y mRNA and somatostatin mRNA in the grafts were due both to an increase in the number of labelled cells and to an increase in the cellular levels of each neuropeptide mRNA. In contrast, the cellular levels of proenkephalin mRNA, prodynorphin mRNA and preprotachykinin mRNA in the grafts were comparable, or elevated relative, to those in the intact striata but the density of cells expressing each of these mRNAs was reduced. Since neuropeptide Y and somatostatin are known to be present in medium to large aspiny striatal neurons (interneurons) and enkephalin, dynorphin and tachykinin peptides and GABA are localized in medium spiny striatal projection neurons, the above findings would indicate that there is a divergence in the levels of activity between these two neuronal populations in the striatal grafts. Our data suggest that the levels of gene expression and hence the functional neurotransmitter-synthesizing and releasing activity in the grafted neuron are diff

Journal article

Keinanen K, Wisden W, Sommer B, Werner P, Herb A, Verdoorn TA, Sakmann B, Seeburg PHet al., 1990, A family of AMPA-selective glutamate receptors, Science, Vol: 249, Pages: 556-560, ISSN: 0036-8075

Four cloned cDNAs encoding 900-amino acid putative glutamate receptors with approximately 70 percent sequence identity were isolated from a rat brain cDNA library. In situ hybridization revealed differential expression patterns of the cognate mRNAs throughout the brain. Functional expression of the cDNAs in cultured mammalian cells generated receptors displaying alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective binding pharmacology (AMPA = quisqualate greater than glutamate greater than kainate) as well as cation channels gated by glutamate, AMPA, and kainate and blocked by 6,7-dinitroquinoxaline-2,3-dione (CNQX).

Journal article

Wisden W, Errington ML, Williams S, Dunnett SB, Waters C, Hitchcock D, Evan G, Bliss TV, Hunt SPet al., 1990, Differential expression of immediate early genes in the hippocampus and spinal cord, Neuron, Vol: 4, Pages: 603-614, ISSN: 0896-6273

We have demonstrated that immediate early genes can be differentially activated within the central nervous system. We examined the effects of tetanic stimulation in the hippocampus and of noxious sensory stimulation of the spinal cord on the expression of eight immediate early genes. Induction of long-term potentiation (LTP) in the dentate gyrus resulted in an increase in mRNA and protein for NGFI-A (also termed Zif/268, Egr-1, or Krox 24), and less consistently for jun-B mRNA. No increase was seen for c-fos, NGFI-B, c-jun, jun-D, SRF, or PC4 mRNAs. Blockade of the NMDA receptor prevented the induction of both LTP and NGFI-A mRNA in the dentate gyrus. However, commissural stimulation, which prevented the induction of LTP, resulted in bilateral activation of all the genes examined, including NGFI-A. No change was seen in animals trained in a water maze. These results suggest that no simple relationship exists between LTP, spatial learning, and immediate early gene induction. Stimulation of sensory fibers resulted in an increase in mRNA for NGFI-A, c-fos, SRF, NGFI-B, and c-jun in spinal cord neurons. Blockade of the NMDA receptor had no effect on immediate early gene induction in the spinal cord.

Journal article

Rusak B, Robertson HA, Wisden W, Hunt SPet al., 1990, Light pulses that shift rhythms induce gene expression in the suprachiasmatic nucleus, Science, Vol: 248, Pages: 1237-1240, ISSN: 0036-8075

Journal article

Sommer B, Keinanen K, Verdoorn TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PHet al., 1990, Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS, Science, Vol: 249, Pages: 1580-1585, ISSN: 0036-8075

In the central nervous system (CNS), the principal mediators of fast synaptic excitatory neurotransmission are L-glutamate-gated ion channels that are responsive to the glutamate agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA). In each member of a family of four abundant AMPA receptors, a small segment preceding the predicted fourth transmembrane region has been shown to exist in two versions with different amino acid sequences. These modules, designated "flip" and "flop," are encoded by adjacent exons of the receptor genes and impart different pharmacological and kinetic properties on currents evoked by L-glutamate or AMPA, but not those evoked by kainate. For each receptor, the alternatively spliced messenger RNAs show distinct expression patterns in rat brain, particularly in the CA1 and CA3 fields of the hippocampus. These results identify a switch in the molecular and functional properties of glutamate receptors operated by alternative splicing.

Journal article


Conference paper

Wisden W, Morris BJ, Darlison MG, Hunt SP, Barnard EAet al., 1989, Differential distribution in bovine brain of distinct GABA-A receptor alpha subunit mRNAs., Biochem Soc Trans (London), Vol: 17, Pages: 566-567

Journal article

Wisden W, Morris BJ, Darlison MG, Hunt SP, Barnard EAet al., 1989, Differential distribution in bovine brain of distinct GABA-A receptor alpha subunit mRNAs., Biochem Soc Trans (London), Pages: 566-567

Book chapter

Darlison MG, Barnard EA, Bateson AN, Glencorse TA, Harvey RJ, Hicks AA, Hunt SP, Morris BJ, Vallejo M, Vreugdnhil E, Wisden Wet al., 1989, The structure and expression of the GABA-A receptor as deduced by molecular genetic studies., In Molecular Biology of Neuroreceptors and Ion Channels, Editors: Maelicke, Publisher: Springer-Verlag, Heidelberg, Pages: 83-99

Book chapter

Wisden W, McNaughton LA, Darlison MG, Hunt SP, Barnard EAet al., 1989, Differential distribution of GABAA receptor mRNAs in bovine cerebellum--localization of alpha 2 mRNA in Bergmann glia layer, Neurosci Lett, Vol: 106, Pages: 7-12

Using in situ hybridization histochemistry, we have demonstrated that 3 alpha subunit mRNAs of the GABAA receptor are present in different cell populations of the bovine cerebellum. While the alpha 1 mRNA is the most abundant and is present in granule cells, Purkinje cells and stellate/basket cells, the alpha 2 mRNA appears to be confined to the Bergmann glial cell layer. The alpha 3 mRNA is only expressed in the Golgi cells. This differential distribution of GABAA receptor mRNA subtypes suggests a previously unrecognized complexity of GABAergic transmission in the cerebellum.

Journal article

Morris BJ, Wisden W, Dunnett SB, Sirinathsinghji DJet al., 1989, Cellular localisation of somatostatin mRNA and neuropeptide Y mRNA in foetal striatal tissue grafts, Neurosci Lett, Vol: 103, Pages: 121-126, ISSN: 0304-3940

Using in situ nucleic acid hybridisation histochemistry, we have studied the expression of somatostatin mRNA and neuropeptide Y mRNA in grafts of embryonic striatal neurones implanted into the ibotenic acid-lesioned rat neostriatum. Tissue sections of the grafted striatum were incubated with either 32P- or 35S-labelled complementary oligodeoxyribonucleotide probes specific for somatostatin mRNA and neuropeptide Y mRNA, exposed with X-ray film and dipped in Ilford K-5 emulsion. Neither somatostatin mRNA nor neuropeptide Y mRNA was detectable in the ibotenic acid-lesioned striatum indicating a pronounced degeneration of somatostatin- and neuropeptide Y-containing neurones. However, in the striatal grafts the levels of somatostatin mRNA and neuropeptide Y mRNA were substantially increased over those in the control intact striata. The results suggest that in the grafts, somatostatin mRNA and neuropeptide Y mRNA were expressed in a higher proportion of primordial striatal neurones and there was also an increased level of expression of each neuropeptide gene per individual neurone (reflecting a higher synthetic activity of such neurones) compared to the intact mature striatum. These data demonstrate the sensitivity of the in situ hybridisation technique to study patterns of gene expression in developing neuronal tissues after transplantation.

Journal article

Wisden W, Morris BJ, Darlison MG, Hunt SP, Barnard EAet al., 1989, Localization of GABA-A receptor alpha-subunit mRNAs in relation to receptor subtypes, Brain Res Mol Brain Res, Vol: 5, Pages: 305-310, ISSN: 0169-328X

The distribution of 3 GABAA receptor alpha-subunit mRNAs in various regions of bovine brain has been investigated using in situ hybridization. Whereas the alpha 2- and alpha 3-transcripts are of low abundance in all regions except striatum, the alpha 1-transcript is considerably enriched in the inferior colliculus, olfactory bulb and substantia nigra, and appears to be correlated with benzodiazepine type I receptor localization.

Journal article

Hunt SP, Wisden W, Morris BJ, Davies SW, Spillantini MG, Goedert Met al., 1989, In situ hybridization in the vertebrate nervous system., Neuropeptides: a Methodology, Editors: Fink, Harmer, Publisher: John Wiley & Sons Ltd, Pages: 55-82

Book chapter

Wisden W, Morris BJ, Darlison MG, Hunt SP, Barnard EAet al., 1988, Distinct GABAA receptor alpha subunit mRNAs show differential patterns of expression in bovine brain, Neuron, Vol: 1, Pages: 937-947, ISSN: 0896-6273

Specific oligonucleotide probes have been used to visualize the regional and cellular distribution of the mRNAs encoding three structurally distinct GABAA receptor alpha subunits in bovine brain. In situ hybridization analysis showed that these transcripts differ in distribution and in relative abundance. In frontal cortex the alpha 1 and alpha 2 transcripts are most abundant in layers II-IV, whereas the alpha 3 mRNA is most abundant in layers V and VI. In the hippocampal complex, the alpha transcripts are differentially distributed in the entorhinal cortex and subiculum. The alpha 2 transcript is enriched in the dentate gyrus and CA4/CA3 regions of the hippocampus. In the cerebellum, essentially only the alpha 1 transcript is detectable in granule cells, Purkinje cells, and stellate/basket cells. These results suggest that the different alpha subunits represent components of distinct GABAA receptor subtypes.

Journal article

Levitan ES, Schofield PR, Burt DR, Rhee LM, Wisden W, Kohler M, Fujita N, Rodriguez HF, Stephenson A, Darlison MG, Barnard EA, Seeburg PHet al., 1988, Structural and functional basis for GABAA receptor heterogeneity, Nature, Vol: 335, Pages: 76-79, ISSN: 0028-0836

When gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in vertebrate brain, binds to its receptor it activates a chloride channel. Neurotransmitter action at the GABAA receptor is potentiated by both benzodiazepines and barbiturates which are therapeutically useful drugs (reviewed in ref. 1). There is strong evidence that this receptor is heterogeneous. We have previously isolated complementary DNAs encoding an alpha- and a beta-subunit and shown that both are needed for expression of a functional GABAA receptor. We have now isolated cDNAs encoding two additional GABAA receptor alpha-subunits, confirming the heterogeneous nature of the receptor/chloride channel complex and demonstrating a molecular basis for it. These alpha-subunits are differentially expressed within the CNS and produce, when expressed with the beta-subunit in Xenopus oocytes, receptor subtypes which can be distinguished by their apparent sensitivity to GABA. Highly homologous receptor subtypes which differ functionally seem to be a common feature of brain receptors.

Journal article

Ma Y, Miracca G, Yu X, Harding EC, Miao A, Yustos R, Vyssotski AL, Franks NP, Wisden Wet al., Galanin neurons in the hypothalamus link sleep homeostasis, body temperature and actions of the α2 adrenergic agonist dexmedetomidine

<jats:title>Abstract</jats:title><jats:p>Sleep deprivation induces a characteristic rebound in NREM sleep accompanied by an immediate increase in the power of delta (0.5 - 4 Hz) oscillations, proportional to the prior time awake. To test the idea that galanin neurons in the mouse lateral preoptic hypothalamus (LPO) regulate this sleep homeostasis, they were selectively genetically ablated. The baseline sleep architecture of <jats:italic>LPO</jats:italic>-Δ<jats:italic>Gal</jats:italic> mice became heavily fragmented, their average core body temperature permanently increased (by about 2°C) and the diurnal variations in body temperature across the sleep-wake cycle also markedly increased. Additionally, <jats:italic>LPO</jats:italic>-Δ<jats:italic>Gal</jats:italic> mice showed a striking spike in body temperature and increase in wakefulness at a time (ZT24) when control mice were experiencing the opposite - a decrease in body temperature and becoming maximally sleepy (start of “lights on”). After sleep deprivation sleep homeostasis was largely abolished in <jats:italic>LPO</jats:italic>-Δ<jats:italic>Gal</jats:italic> mice: the characteristic increase in the delta power of NREM sleep following sleep deprivation was absent, suggesting that LPO galanin neurons track the time spent awake. Moreover, the amount of recovery sleep was substantially reduced over the following hours. We also found that the α2 adrenergic agonist dexmedetomidine, used for long-term sedation during intensive care, requires LPO galanin neurons to induce both the NREM-like state with increased delta power and the reduction in body temperature, characteristic features of this drug. This suggests that dexmedetomidine over-activates the natural sleep homeostasis pathway via galanin neurons. Collectively, the results emphasize that NREM sleep and the concurrent reduction in b

Journal article

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