Photo of Michael Hildebrand

Michael Hildebrand

Phone:613-520-2600 x 3306
Email:Mike.Hildebrand@carleton.ca
Office:106 J Social Sciences Research Building until December 13(ish)
5310 Health Sciences Building after Dec 13(ish)

Eligible to supervise at the undergraduate and graduate level.

Current research in the Hildebrand Lab:

  • Changes in NMDA receptor expression and function during spinal cord development.
  • Use of a novel electrophysiological recording technique to study voltage-gated channel activity in spinal cord neurons.
  • Characterization of voltage-gated calcium channels in the spinal cord dorsal horn.
  • Regulation of NMDA receptor activity during BDNF-mediated pathological pain signalling.
  • Mechanisms of spinal cord hyperexcitability in models of chronic inflammatory pain.

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Area of Research

The inability to effectively treat and manage chronic pain is one of the major public health challenges facing society today.  The spinal cord dorsal horn is a neuronal network within the pain transmission pathway which integrates sensory signals from the periphery and relays processed messages up to brain pain centers.  A myriad of pain-producing factors and events facilitate dorsal horn excitation to cause pain hypersensitivity, yet the underpinning molecular and cellular mechanisms are poorly understood.  My research interests center around the ion channel proteins which control the excitability of dorsal horn spinal cord neurons.  My research group will combine electrophysiological recordings from ex vivo spinal cord slices with genetic, biochemical, pharmacological, and behavioural approaches to explore how the activities of ion channels in dorsal horn neurons are regulated during developmental, physiological, and pathological processes.  Based on my prior academic and industrial research experiences, my laboratory is uniquely prepared to study the two main classes of ion channels which regulate dorsal horn excitability – ligand-gated ion channels and voltage-gated ion channels.

Research Program Cartoon_0

1. Ligand Gated Ion Channels – NMDA Receptors

The NMDA receptor (NMDAR) is a subtype of ionotropic glutamate receptor with unique functional properties, enabling it to integrate synaptic and intercellular signals during mechanisms of neuroplasticity.  NMDAR activity is essential for pathological dorsal horn facilitation, yet the molecular identity and regulation of synaptic NMDARs in dorsal horn neurons remain a mystery.  Using recordings of spontaneous synaptic NMDAR activity, we are investigating how the molecular composition and function of dorsal horn NMDARs are regulated by developmental and pain-amplifying mechanisms as well as how this regulation modulates target effector proteins through downstream biochemical signalling.

2. Voltage-Gated Ion Channels – Sodium (NaV) Channels

Voltage-gated sodium (NaV) channels shape the excitability of neurons throughout the CNS.  Within the pain transmission pathway, abberant sodium channel function causes neuronal hyperexcitability and pain hypersensitivity.  Hence, numerous pain therapeutics used in the clinic reduce NaV channel activity.  However, an understanding of the molecular identity and function of NaV channels in dorsal horn neurons has only started to emerge.  We recently characterized the molecular, biophysical, and pharmacological properties of NaV channels in dorsal horn neurons and found that NaV channels in the spinal cord are highly divergent in composition and function compared to the periphery (Hildebrand et al., 2011a).  Thus, dorsal horn voltage-gated channels form a distinct or complementary potential molecular target for future pain therapeutics.  Through work with the pharmaceutical industry, we identified a novel class of organic compounds that target a specific biophysical state of NaV channels in dorsal horn neurons (Hildebrand et al., 2011b).  These potential therapeutic compounds attenuate dorsal horn excitability and potently reverse pain hypersensitivity (Hildebrand et al., 2011b).  Given these exciting findings, we aim to systematically study how NaV channel activity is regulated within distinct subpopulations of dorsal horn neurons during pain signalling processes.

3. Voltage-Gated Ion Channels – Calcium (CaV) Channels

Voltage-gated calcium (CaV) channels play an essential role in controlling neurotransmitter release from peripheral pain transmission neurons, yet their roles in regulating the excitability of dorsal horn neurons are incompletely understood (Hildebrand and Snutch, 2006).  Pharmacological blockers against specific groups of CaV channels reduce activity-dependent plasticity in dorsal horn neurons, yet the molecular identity and function of CaV channels in dorsal horn neurons is not known.  In the brain, we have found that CaV channel subtypes are specifically and differentially modulated by intercellular signals acting on membrane receptors (Hildebrand et al., 2007; Hildebrand et al., 2009).  In the spinal cord, several inflammatory and neuropathic substances facilitate the excitability of dorsal horn neurons through signalling pathways which include depolarization and the elevation of intracellular calcium.  We aim to characterize the CaV channels subtypes expressed within subpopulations of dorsal horn neurons and explore how their modulation is involved in mechanisms of dorsal horn facilitation.

Publications:

Hildebrand ME, Snutch TP.  (2015) The unusual suspects: Regulation of retinal calcium channels by somatostatin.  Channels 9(2):61-2.
URL: http://www.ncbi.nlm.nih.gov/pubmed/25715059

Hildebrand, ME, Pitcher, GM, Harding, EK, Li, H, Beggs, S, Salter, MW (2014) Dominant GluN2B- and GluN2D-mediated synaptic responses in the adult spinal cord.  Scientific Reports 4: 4094 (12 pages).
URL: http://www.ncbi.nlm.nih.gov/pubmed/24522697

Bourinet, E, Altier, C, Hildebrand, ME, Trang, T., Salter, MW, Zamponi, GW (2014) Calcium permeable ion channels in pain signaling.  Physiological Reviews 94(1): 81-140.
URL: http://www.ncbi.nlm.nih.gov/pubmed/24382884

Isope P, Hildebrand ME, Snutch TP. (2012) Contributions of T-type voltage-gated calcium channels to postsynaptic calcium signalling within Purkinje neurons.  Cerebellum 11(3): 651-665.
http://www.ncbi.nlm.nih.gov/pubmed/20734177

Hildebrand ME, Mezeyova J, Smith PL, Salter MW, Tringham E, Snutch TP. (2011a) Identification of sodium channel isoforms that mediate action potential firing in lamina I/II spinal cord neurons.  Molecular Pain 7(1): 67 (13 pages).
http://www.ncbi.nlm.nih.gov/pubmed/21910862

Hildebrand ME, Smith P, Bladen C, Eduljee C, Xie J, Chen L, Fee-Maki M, Doering C, Mezeyova J, Zhu Y, Belardetti F, Pajouhesh H, Parker D, Parmar M, Porreca F, Tringham E, Zamponi G, Snutch TP. (2011b) A novel slow inactivation specific ion channel modulator attenuates neuropathic pain.  Pain 152(4): 833-843.
http://www.ncbi.nlm.nih.gov/pubmed/21349638

Singh A, Hildebrand ME, Garcia E, Snutch TP. (2010) The TRPC antagonist SKF 96365 is a potent blocker of low voltage–activated T–type calcium channels.  British Journal of Pharmacology 160(6): 1464-75.
http://www.ncbi.nlm.nih.gov/pubmed/20590636

Hildebrand ME, Isope P, Garcia E, Feltz A, Schneider T, Hescheler J, Kano M, Sakimura K, Dieudonné S, Snutch TP. (2009) Functional coupling between mGluR1 and CaV3.1 T-type calcium channels enhances cerebellar purkinje cell excitability and local signaling.  Journal of Neuroscience 29(31): 9668-82.
http://www.ncbi.nlm.nih.gov/pubmed/19657020

Tao J, Hildebrand ME, Liao P, Liang MC, Tan G, Li S, Snutch TP, Soong TW. (2008) Activation of corticotropin-releasing factor receptor 1 selectively inhibits CaV3.2 T-type calcium channels. Molecular Pharmacology 73(6): 1596-1609.
http://www.ncbi.nlm.nih.gov/pubmed/18292205

Hildebrand ME, David LS, Hamid J, Mulatz K, Garcia E, Zamponi GW, Snutch TP. (2007) Selective inhibition of CaV3.3 T-type calcium channels by Gq/11-coupled muscarinic acetylcholine receptors.  Journal of Biological Chemistry 282: 21043-21055.
http://www.ncbi.nlm.nih.gov/pubmed/17535809

Hildebrand ME, Snutch TP. (2006) Contributions of T-Type calcium channels to the pathophysiology of pain signaling.  Drug Discovery Today: Disease Mechanisms 3(3): 335-341.

Vieira LB, Kushmerick C, Hildebrand ME, Garcia E, Stea A, Cordeiro MN, Richardson M, Gomez MV, Snutch TP. (2005) Inhibition of high voltage-activated calcium channels by spider toxin PnTx3-6.  Journal of Pharmacology and Experimental Therapeutics 314(3): 1370-1377.
http://www.ncbi.nlm.nih.gov/pubmed/15933156

Spacey SD, Hildebrand, ME, Materek LA, Bird TD, Snutch TP. (2004) Functional implications of a novel EA2 mutation in the P/Q-type calcium channel.  Annals of Neurology 56(2): 213-220. http://www.ncbi.nlm.nih.gov/pubmed/15293273

Hildebrand, ME, McRory JE, Snutch TP, Stea A. (2004) Mammalian voltage-gated calcium channels are potently blocked by the pyrethroid insecticide allethrin. Journal of Pharmacology and Experimental Therapeutics 308(3): 805-813.
http://www.ncbi.nlm.nih.gov/pubmed/14634047

McRory JE, Hamid J, Doering CJ, Garcia E,  Parker R, Hamming K, Chen L,  Hildebrand M, Beedle A, Feldcamp L, Zamponi GW, Snutch TP. (2004) The CACNA1F gene encodes an L-type calcium channel with unique biophysical properties and tissue distribution. Journal of Neuroscience 24(7): 1707-1718.
http://www.ncbi.nlm.nih.gov/pubmed/14973233