W. Hamish Mehaffey

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W. Hamish Mehaffey PhD
BSc University of Victoria
PhD Neuroscience University of Calgary 2008
PhD Dissertation: Synaptic regulation of burst discharge

Keck Center for Integrative Neuroscience
HSE 804, Box 0444
513 Parnassus Ave
San Francisco CA
whmehaff@phy.ucsf.edu

Training 1999 BSc Psychology University of Victoria Victoria BC	2001 - 2008 PhD Neuroscience University of Calgary Calgary Alberta Supervisor: R.W. Turner	2006 Teaching Asst. - Methods Computational Neuroscience Wood's Hole MA 2007 Teaching Asst. - Computational Neuroscience Ottawa ON
Special Courses 2005 Wood's Hole Marine Biological Laboratories Methods in Computational Neuroscience		2006 Center for Non-linear dynamics, McGill Univ. Non-Linear Dynamics in Physiology and Medicine

Awards
MSc
Province of Alberta Graduate Scholarship
Faculty of Gradute Studies Scholarship
Alberta Learning Scholarship

PhD
CIHR Doctoral Award
Dean's Research Excellence Award
AHFMR Studentship
Society Neuroscience Chapter Graduate Student Travel Award

PDF
Grass Fellowship - Independent Project at Wood's Hole MA
CIHR Postdoctoral Fellowship, UCSF

Research Focus: The synaptic regulation of input-output relations

Approach:

I use a combination of intracellular recordings in vitro and conductance-based modeling to determine the relative contribution of voltage- or ligand-gated channels to the input-output relation of ELL pyramidal cells.

Techniques:

In vitro slice preparations, computational neuroscience

Below are short summaries of my projects published from the lab.

Model - ELL pyramidal cell burst discharge
Pyramidal cells of the electrosensory lobe (ELL) of weakly electric fish encode modulations in external electric fields by generating spike bursts. These bursts arise by a "conditional backpropagation" of sodium spikes from the soma and over the proximal apical dendrites that re-excite the soma as a depolarizing afterpotential (DAP). A frequency-dependent mismatch in refractory period between soma and dendrite leads to burst discharge through a cyclic failure of backpropagation. PDF

Obtaining patch clamp recordings in the adult CNS
Patch clamp recordings are often difficult to obtain beyond P17 due to a peri-neuronal net in the extracellular space. I helped develop a method of "spread-printing", a novel approach to partially dissociate tissue slices and remove the peri-neuronal net. We showed that spread-printing allows recordings from identified cells down to the single channel level in animals that are months old without the need for proteolytic enzymes. See Morales et al. (2004). PDF

Kv3 potassium channels exhibit frequency-dependent effects on cell output
This study describes a frequency-dependent effect of high threshold Kv3 potassium channels on the input-output relation of pyramidal cells and determined its underlying basis. A combination of patch recordings and modeling show that Kv3 channels rescue spike trains at high frequencies by decreasing both sodium channel inactivation and a cumulative increase in a low threshold potassium current. See Fernandez et al. (2005) PDF

Kv1 K+ channels regulate the climbing fiber EPSP

Kv1 potassium channels optimize rebound discharge in deep cerebellar neurons
In this study we examined the role of low threshold Kv1 K+ channels in controlling Purkinje cell discharge and its effect on the activity of postsynaptic deep cerebellar neurons. We show that Kv1 channels lower Na+ spike frequency and raise the threshold for Ca2+ spike discharge. When these spike patterns are applied as stimulus templates to Purkinje cell axons, we found that Kv1 channels lower Purkinje cell output frequency to a range that optimizes rebound discharge in deep cerebellar neurons. See McKay et al. (2005) PDF

A decrease in dendritic excitability can increase cell output
This study describes how a progressive inactivation of dendritic Na+ channels during repetitive activity can shift the relation between somatic and dendritic spike timing. A progressive delay in dendritic spike latency increases its effectiveness at generating a depolarizing afterpotential at the soma, leading to a paradoxical increase in somatic spike output in the face of a decrease in dendritic excitability. See Fernandez et al. (2005) PDF

Dendritic inhibition mediates a deterministic gain control
This study describes a novel mechanism of multiplicative gain control that involves active dendritic membrane. Most gain control mechanisms require noisy inputs, however this mechanism allows a modulation of gain in a purely deterministic fashion. This allows gain control in the absence of the deleterious effects of noise. See Mehaffey et al. (2005) PDF

Measurement of stellate first spike latency

A-type K+ and T-type Ca2+ channels generate a novel first spike latency relationship
In this study we examined the mechanism underlying a non-monotonic voltage - first spike latency relationship in cerebellar stellate cells. We show through current and voltage clamp analysis and modeling that A-type and T-type inactivating channels interact to produce a voltage-dependent increase or decrease in first spike latency. The effect depends critically on the voltage-dependence of inactivation and relative density of the respective currents. See Molineux et al. (2005) PDF

Rebound burst discharge in deep cerebellar neurons

T-type Ca2+ channel isoforms correlate with distinct burst phenotypes
In this study we determined the distribution of the three isoforms of T-type currents (Cav3.1, 3.2, 3.3) in rat cerebellar neurons, revealing a greater range of expression and contribution to rebound discharge than realized. Moreover, a distinct expession pattern for Cav3 isoforms in deep cerebellar nuclear neurons is shown to correlate to either a strong or weak rebound discharge capability. See Molineux et al. (2006). PDF

CF discharge converts Purkinje cell output

Climbing fiber input regulates intrinsic properties of Purkinje cells
In this study we show that climbing fiber input activated at physiological frequencies blocks an intrinsic trimodal pattern inherent to Purkinje cells studied in vitro, restoring tonic Na+ spike discharge similar to that found in vivo. Moreover, all the effects of direct climbing fiber stimulation were reproduced by simulating climbing fiber input with an injected EPSC in the presence of synaptic blockers, emphasizing a key role for the postsynaptic complex spike depolarization in determining Purkinje cell activity. See McKay et al. (2007).

Dendritic GABA-B activation promotes burst discharge

Dendritic GABA-B receptors delay dendritic spikes to enhance burst output
In this study I show that activation of dendritic GABAB receptors by a feedback inhibitory pathway delays the onset of a backpropagating dendritic spike to shift the soma-dendritic temporal relationship in spike discharge. A resulting increase in burst output ultimately serves to increase spike train segregation to improve the encoding of fast frequency inputs. See Mehaffey et al. (2007).

SK channel-mediated AHPs differentially regulate frequency tuning
This study describes how a selective expression of SK2 channels can shift the frequency preference of principle sensory neurons. By regulating burst discharge, somatic SK2 channels selectively decrease the low-frequency response of ELL pyramidal cells, creating a comparatively broadband response. In support of this, SK2 channel expression is localized to cells that exhibit broadband frequency responses but is absent in cells with a low-frequency preference. See Ellis, Mehaffey et al. (2007).

Pyramidal cell firing characteristics differ across multiple sensory maps
The ELL of weakly electric fish has multiple sensory maps that have specific behavioural functions related to their frequency tuning. In this study we show that the intrinsic spike generating mechanism can contribute significantly to determining which specific frequency components of a broadband input a neuron responds to. As such, it reveals a direct relationship between ion channels controlling spike discharge and sensory processing. See Mehaffey et al. (2008).

Distinct ion channel contributions to burst phenotype in deep cerebellar neurons
The large diameter putative projection neurons of rat deep cerebellar nuclei have been shown to generate either a Transient or Weak rebound Burst phenotype that was linked to the selective expression of T-type calcium channel isoforms. Here we show that the two burst phenotypes also reflect a differential functional availability of LVA T type calcium current at burst threshold, and different contributions of repolarizing potassium currents that shape burst properties. See Molineux et al. (2008). PDF

Synaptically evoked rebound bursts in deep cerebellar neurons
Rebound burst discharge in deep cerebellar nuclear (DCN) cells is readily evoked through direct current injection, but the probability of evoking rebounds with inhibitory synaptic stimulation is less certain. Here we show that stimulation of Purkinje cell inhibitory inputs to DCN neurons in vitro evokes rebound bursts that can be distinguished according to two known phenotypes of burst output. Reliable rebound burst generation can be evoked with moderate stimulus intensities, indicating the potential for this activity to contribute to cerebellar output in response to physiological activity in vivo. See Tadayonnejad et al. (2009). PDF

Peer-reviewed Publications

Morales E, Fernandez FR, Sinclair S, Molineux ML, Mehaffey WH and Turner RW. (2004) Releasing the peri-neuronal net to patch clamp neurons in the adult CNS. Pflugers Archiv 448(2): 248-58. PDF

McKay BE , Molineux ML, Mehaffey WH and Turner RW. (2005) Kv1 potassium channels control Purkinje cell output to facilitate post-synaptic rebound discharge in deep cerebellar neurons. J. Neuroscience 25(6): 1481-1492. PDF

Fernandez FR*, Mehaffey WH*, Molineux ML and Turner RW. (2005) High threshold potassium channels increase gain by offsetting a frequency-dependent increase in low threshold potassium current. (*shared first author) J. Neuroscience 25(2): 363-371. PDF

Fernandez FR, Mehaffey WH and Turner RW. (2005) Dendritic Na+ current inactivation can increase cell excitability by delaying a somatic depolarizing afterpotential. J. Neurophysiology 94: 3836-3848.PDF

Mehaffey WH, Doiron B, Maler L and Turner RW. (2005) Deterministic multiplicative gain control with active dendrites. J. Neuroscience 25(43): 9968-9977. PDF

Molineux ML*, Fernandez FR*, Mehaffey WH and Turner RW (2005) A-type and T-type currents interact to produce a novel spike latency-voltage relationship in cerebellar stellate cells. J. Neuroscience 25(47): 10863-10873. * Shared first author. PDF

Molineux ML, McRory JE, McKay BE, Hamid J, Mehaffey WH, Snutch TP, Zamponi GW and Turner RW (2006) Specific T-type calcium channel isoforms are associated with distinct burst phenotypes in deep cerebellar nuclear neurons. PNAS 103(14): 5555-5560. PDF Supplementary data

McKay BE, Engbers JT, Mehaffey WH, Gordon G, Molineux ML, Bains J and Turner RW (2007) Climbing fiber discharge regulates cerebellar functions by controlling the intrinsic characteristics of Purkinje cell output. J. Neurophysiology 97: 2590-2604. PDF

Mehaffey WH, Fernandez FR, Maler L and Turner RW (2007) Regulation of burst dynamics improves differential encoding of stimulus frequency by spike train segregation. J. Neurophysiology 98(2): 939-951. PDF

Ellis L*, Mehaffey WH*, Harvey-Girard E, Turner RW, Maler L and Dunn RJ (2007) SK channels provide a novel mechanism for the control of frequency tuning in electrosensory neurons. J. Neuroscience 27 (35): 9491-9502. *Shared first author. PDF

Mehaffey, W.H., Maler, L. and Turner, R.W. (2008) Intrinsic frequency tuning in ELL pyramidal cells varies across electrosensory maps. J. Neurophysiology 99(5): 2641-2655. PDF

Molineux, M.L., Mehaffey, W.H., Tadayonnejad, R., Anderson, D., Tennent, A.F. and Turner, R.W. (2008) Ionic factors governing rebound burst phenotype in rat deep cerebellar neurons. J. Neurophysiology 100:2684-2701. PDF

Tadayonnejad, R., Mehaffey, W.H., Anderson, D. and Turner, R.W. (2009) Reliability of triggering postinhibitory rebound bursts in deep cerebellar neurons. Channels 3(3):149-155. PDF

Anderson, D.M., Mehaffey, W.H., Iftinca, M., Rehak, R., Engbers, J.D.T., Hameed, S., Zamponi, G.W. and Turner, R.W. (2010) Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes. Nature Neuroscience, In Press. Link

Invited Chapters

Mehaffey WH*, Fernandez FR*, Rashid AJ, Dunn RJ and Turner RW (2006) The distribution and function of potassium channels in aperonotid electrosensory lateral line lobe. J. Comp. Physiol. A, Neuroethol Sens Neural Behav Physiol. 20:1-12. (*shared first author) PDF

Mehaffey WH, Fernandez FR, Doiron B, and Turner RW. (2008) Regulation of somatic firing dynamics by backpropagating dendritic spikes. J. Physiol. (Paris) 102: 181-194. PDF

Mehaffey WH*, Ellis LD*, Krahe R, Maler L, Dunn RJ and Chacron MJ. (2008) Ionic and neuromodulatory regulation of burst discharge. J. Physiol. (Paris) 102: 195–208. *Shared Authorship. PDF

Invited Talks
- 2005 - Deterministic Multiplicative Gain Control From Active Dendrites, Computational Neuroscience 2005, Madison, WI.

- 2006 - Burst regulation alters spike segregation in the ELL of electric fish, Institute for Theoretical Biology, Humboldt University, Berlin.

- 2007 - Regulation of spike train segregation in electrosensory processing, Stanford University, CA.

Key Abstracts
Fernandez FR, Mehaffey WH, Rashid AJ, Dunn RJ and Turner RW. Kv3 channel contribution to repetitive spike activity. Ann Proc Soc Neurosci 2003.

Fernandez FR, Mehaffey WH, Molineux ML and Turner RW. High threshold K+ channels increase gain by offsetting a cumulative activation of low threshold K+ current. Ann Proc Soc Neurosci, 2004.

Mehaffey WH, Doiron B, Maler L and Turner RW. Deterministic multiplicative gain control by active dendrites. Ann Proc Soc Neurosci, 2004.

Fernandez FR, Mehaffey WH and Turner, RW. Dendritic Na+ current inactivation can increase cell excitability by delaying a somatic depolarizing afterpotential. Proc Soc Neurosci 2005.

Mehaffey WH, Fernandez FR, and Turner RW. Inhibitory GABA-B conductances cause a shift to burst firing mode. Proc Soc Neurosci, 2005.

Mehaffey WH, Fernandez FR and Turner RW. Inhibitory Dendritic GABAb Conductances can Shift Cells to Burst Firing in the ELL of electric fish. Comp Neurosci (CNS) 2006.

Mehaffey WH, Fernandez FR and Turner RW. Burst regulation regulates spike train segregation in the ELL of electric fish.Proc Soc Neurosci, 2006.

Mehaffey WH, Maler L and Turner RW. Feedback modulation of intrinsic firing dynamics restores feature detection in electrosensory processes. Comp Neurosci (CNS) 2007.

McKay BE, Engbers JDT, Mehaffey WH, Gordon GRJ, Molineux ML, Bains JS and Turner, RW. Climbing fibre control of Purkinje cell spike output. Can Assoc Neurosci 2007 [Can J. Neurol. Sci., 34 (Supplement 3): S87].

Molineux ML, Tennent AF, Mehaffey WH and Turner RW. Ionic mechanisms of spike firing in two distinct types of rat deep cerebellar neurons. Proc. Soc. Neurosci. 2007.

Tadayonnejad R, Molineux ML, Mehaffey WH and Turner RW. Transient and Weak Bursting Deep Cerebellar neurons exhibit differential coding properties for membrane hyperpolarizations. Proc. Soc. Neurosci. 2007.

Mehaffey WH, Maler L and Turner RW. Distribution of intrinsic and bursting properties of basilar and non-basilar pyramidal cells across the maps of the electrosensory lateral line lobe. Proc. Soc. Neurosci. 2007.

Tadayonnejad R, Mehaffey WH, Jayasuriya K and Turner RW. Rate and temporal coding properties of deep cerebellar neurons. Can. Assoc. Neurosci. 2008.

Mehaffey WH and Turner R.W. Feedback modulation of firing dynamics restores feature detection in electrosensory processing. Can. Assoc. Neurosci. 2008.

Engbers, J.D.T., Mehaffey, W.H., Fernandez, F.R. and Turner, R.W. Synaptic noise modulates the probability of climbing fibre-induced state transitions in cerebellar Purkinje cells. Proc. Soc. Neurosci. 2008.

Tadayonnejad, R., Mehaffey, W.H. and Turner, R.W. Deep cerebellar nuclear neurons use different strategies for coding physiological patterns of Purkinje cell activity. Proc. Soc. Neurosci. 2008.

Mehaffey, W.H. and Turner, R.W. Interaction between network and intrinsic oscillatory dynamics in electrosensory processing. Proc. Soc. Neurosci. 2008.

Tadayonnejad, R., Mehaffey, W.H., Jayasuriya, K. and Turner, R.W. Rebound burst phenotypes in Deep Cerebellar Nuclear cells define the response to synaptically evoked mem brane hyperpolarizations. Can Assoc. Neurosci. 2009.

Anderson, D.M., Mehaffey, W.H., Engbers, J.D.T., Rehak, R., Hamid, S., Zamponi, G.W. and Turner, R.W. T-type mediated calcium influx dynamically modulates Kv4 inactivation. Can Assoc. Neurosci. 2009.

Engbers, J.D.T., Mehaffey, W.H. Fernandez, F.R. and Turner, R.W. Synaptic noise modulates the probability of climbing fibre-induced state transitions in cerebellar Purkinje cells. Can Assoc. Neurosci. 2009.

Engbers, J.D.T., Mehaffey, W.H. Fernandez, F.R. and Turner, R.W. Synaptic noise modulates the probability of climbing fiber-induced state transitions in cerebellar Purkinje cells. IUPS, Kyoto 2009.

Anderson, D.M., Mehaffey, W.H., Rehak, R., Hamid, S., Zamponi, G.W. and Turner R.W. A-type potassium channels are dynamically regulated by T-type calcium current. IUPS, Kyoto 2009.

Tadayonnejad, R., Mehaffey, W.H. and Turner, R.W. Rate and temporal neural codes in deep cerebellar neurons translate Purkinje cell inhibitory input. IUPS, Kyoto 2009.