Stuart Mangel, Ph.D.March 27, 2015 Professor, Dept. of Neuroscience BIOPHYSICS 6702 – ENCODING NEURAL INFORMATION IN THE RETINA AND BRAIN I. Basic Features of Principal Retinal Circuits a. photoreceptor cells hyperpolarize to light b. horizontal cells hyperpolarize to light (sign-conserving synapse) c. Depolarizing and hyperpolarizing bipolar cells (sign-conserving and sign-inverting synapses) d. Receptive field structure of bipolar cells (center-surround organization; horizontal cells provide receptive field surround using lateral inhibition) e. Receptive field structure of ganglion cells (generation of action potentials; center- surround organization; perceived brightness contrast) f. Parallel processing (“trigger” features; non-linear response mechanisms) - amacrine cells (e.g. starburst amacrine cells) - ganglion cells (e.g. transient vs. sustained; directionally selective, etc.)

On-Bipolar Cells Stimulus Spot (Center) Horizontal CellsOff-Bipolar Cells Annulus ( Surround) Spot + Annulus Horizontal cells provide the receptive field surround to bipolar cells

Synaptic connections that produce the center-surround receptive field organization of bipolar cells Bipolar cell receptive field OFF-BC: Hyperpol ON-BC: Depol OFF-BC: Depol ON-BC: Hyperpol Cones hyperpolarize Cones hyperpolarize Horizontal cells hyperpolarize Light stimulation over small, central retinal area Light stimulation over larger, surrounding retinal area excitatory (“sign-conserving”) synapse inhibitory (“sign-inverting”) synapse

Synaptic connections that produce the center-surround receptive field organization of bipolar cells Bipolar cell receptive field OFF-BC: Hyperpol ON-BC: Depol OFF-BC: Depol ON-BC: Hyperpol Cones hyperpolarize Cones Depolarize Cones hyperpolarize Horizontal cells hyperpolarize Light stimulation over small, central retinal area Light stimulation over larger, surrounding retinal area excitatory (“sign-conserving”) synapse inhibitory (“sign-inverting”) synapse

Na + K+K+ 2Cl - GABA Cl - GABA A receptor Na-K-2Cl (NKCC) GABA-Evoked Depolarization K+K+ Cl - GABA GABA A receptor Cl - K-Cl (KCC) GABA-Evoked Hyperpolarization Cl - ON-BC DENDRITEOFF-BC DENDRITE 1. The GABA released from horizontal cells depolarizes ON-BC dendrites, but hyperpolarizes OFF-BC dendrites. 2. The chloride cotransporters, Na-K-2Cl (NKCC) and K-Cl (KCC), determine whether GABA A receptor activation, which opens Cl - channels, depolarizes or hyperpolarizes neurons, respectively. Cl -

Receptive field profiles of ganglion cell subtypes X-type ganglion cell Y-type ganglion cell

- from Barlow and Levick, 1965 ON-OFF direction selective ganglion cells

Response properties of ON-OFF direction selective ganglion cells

Models of direction selectivity in the retina

ROLE OF ION TRANSPORTERS IN NEURAL NETWORK FUNCTION Fig. 2. The dendrites of starburst amacrine cells (green), a type of interneuron in the retina, hyperpolarize to light stimuli that move from the periphery to the cell body (bottom left) and depolarize to light stimuli that move from the cell body to the periphery (bottom right). These directionally-selective responses are generated in part by the differential distribution of the Na-K-2Cl (NKCC) cotransporter (pink) on the cell body and proximal dendrites and the K-Cl (KCC2) cotransporter (blue) on the distal dendrites. The expression patterns of Na-K-2Cl and K-Cl are represented as pink to purple and purple to blue gradients, respectively, on the dendrites and cell body of this starburst cell. GABA-evoked depolarization GABA-evoked hyperpolarization Fig. 1. The chloride cotransporters, Na-K-2Cl (NKCC) and K-Cl (KCC2), determine whether the neurotransmitter GABA, which opens Cl - channels, depolarizes or hyperpolarizes neurons, respectively. Fig. 1 Fig. 2 - modified from Gavrikov et al., 2006, PNAS Fig. 3. The GABA reversal potential at the starburst amacrine cell (SAC) distal dendrite is more hyperpolarized than at the proximal dendrite due to KCC2 activity. (A, B) GABA was applied onto the proximal dendrite (A) and onto the distal dendrite (B) ~ 100  m from the cell body of a SAC in the presence of cobalt (2 mM) to block synaptic transmission. (C) Average E GABA of the proximal and distal dendrites of SACs were significantly different (p < 0.01). (D) Average E GABA of distal dendrites before and during bath application of FUR (25  M), a selective inhibitor of KCC2 activity, were significantly different (p < 0.01). Fig. 3

A MODEL OF DIRECTION SELECTIVITY IN THE RETINA - modified from Gavrikov et al., 2003, PNAS

Ribelayga, Cao & Mangel, 2008, Neuron Rod pathways at night under dark conditions The circadian (24-hr) clock in the retina increases the electrical coupling of rod-cone gap junctions at night

Readings for Biophysics 6702 – Lectures on March 25/27, 2015: Kandel, Schwartz, Jessell, Siegelbaum & Hudspeth, 2013, Principles of Neural Science, 5 th Ed., Chapters 21, 26 Masland, 2004, Direction Selectivity Gavrikov, Nilson, Dmitriev, Zucker & Mangel, 2006, PNAS Fried, Munch & Werblin, 2002, Nature