Research

Forms follow function: functional impact of diverse synaptic morphologies within a particular area or region.

Nishant Singh

Synaptic morphologies display various distinct designs across brain regions and within a brain region. The Schaffer collaterals synapse (between CA3 and CA1 neurons) in the hippocampus, is a small but important synapse involved in episodic memory formation & spatial navigation, and it has a single release site for neurotransmitters. The mossy fiber terminal, on the other hand, between dentate gyrus and CA3, is a giant synapse, ~1000 times larger in volume than the CA3 terminal, has multiple release sites on to the same postsynaptic neuron. In physiologically realistic 3D models of synapses, we ask what distinctive features these ‘design quirks’ bring to the table. More specifically, what is the contribution of these uniquely evolved designs to synaptic function and ultimately memory formation? To achieve this, our lab adopts a methodology that involves developing intricate biophysical computational models, enabling 'in-silico' experimentation, and generating empirically testable hypotheses to derive fundamental principles that govern brain function.

Metaplasticity of the hippocampal synapses 

Gaurang Mahajan

Information is processed and stored as memories in the brain in the form of changes in the connection strengths between them. Hippocampal synapses are highly plastic and are thought to be a crucial component of learning. The strength of connections (synapses) that encode information progressively increases and ultimately saturates. These synapses can then no longer encode information. Given the limited number of available synapses, saturation limits the storage capacity of the hippocampal network. Along with homeostatic plasticity, we also like to think about Metaplastcity or plasticity of plasticity that might occur over shorter timescales as opposed to homeostatic mechanisms. We ask how synapses with saturated strengths could be brought back into the game of encoding information via available intracellular mechanisms over behavioral timescales.

Dysregulation of calcium signaling in Alzheimer’s disease (AD) 

Surabhi Sinha and Nishant Singh

Calcium signaling regulates synaptic transmission and all forms of plasticity considered to be the substrate of learning and memory. In addition to its role in neurotransmitter release and synaptic plasticity, calcium triggers numerous downstream chemical signaling pathways that are essential for information processing in the brain and the formation of memories. However, multiple lines of evidence indicate that calcium signaling is impaired in Alzheimer's disease (AD) and may represent one of the earliest indicators of pathological decline, disrupting normal synaptic plasticity mechanisms and interfering with the consolidation of memories. Based on experimental evidence, we investigate the various ways by which calcium signaling can be disrupted in AD. We would like to determine the chronology of events that may ultimately disrupt both long-term and short-term plasticity as seen in AD. For this purpose, we use a detailed biophysical, spatial, and stochastic computational model of the CA3-CA1 synapse of the hippocampus.

Modeling the effect of acetylcholine as a neuromodulator in synaptic function 

Rohan Sharma 

Cholinergic modulation has been observed to be very closely associated with memory formation and retrieval.However a complete quantitative picture of the changes in the biochemistry triggered by acetylcholine that modifies synaptic plasticity does not exist. Neuromodulatory signals differ from canonical neurotransmitters like glutamate or gamma-aminobutyric acid (GABA). Neuromodulation, in contrast with fast and focused postsynaptic consequences of ‘neurotransmission’ plays out over longer spatial and temporal scales. Acetylcholine, in particular, is elevated during periods of active wakefulness, where it is often coincident with theta-modulation from the medial septum. We look at the role of acetylcholine in altering CA3-CA1 synaptic dynamics during active-waking periods.

Investigating the generation and disruption of alpha rhythms

Sumanth Athreya

Hebbian plasticity mechanisms, such as long-term potentiation and long-term depression, can set off a positive feedback loop where strong synapses can get stronger (and weak, weaker), enhancing the overall firing rate (or lowering the overall rate). This can disrupt the stability of neuronal firing. Homeostatic plasticity curbs the snowball effect of the Hebbian plasticity mechanism important for the normal function of the brain. If information is stored in the relative changes of synaptic strengths, then any homeostatic changes must retain the local modifications while adjusting global activity rates to maintain a stable level of activity. After homeostatic modifications have taken place, we simulate the observed changes in the presynaptic and postsynaptic terminals of 3D computational models of Schaffer collaterals. We ask how these changes affect the synaptic transmission,  Hebbbian plasticity, and information/energy balance at these synapses. 

Modeling astrocytic contribution to synaptic signaling 

Shweta Shrotri and Anup Pillai

Over the past two decades, there has been a shift from a "neurocentric" view of brain function to a more comprehensive understanding that includes the role of glial cells. Seminal research from various laboratories has established the critical functions of astrocytes (a subtype of glia)  in brain development, energy regulation through vasculature coupling, and information processing and storage. Astrocytes have also been implicated in several diseases. Astrocytes express a diverse range of transmitter receptors, and when neurotransmitters bind to these receptors, they trigger a calcium response that can lead to the release of gliotransmitters. In the hippocampus's CA1 region, over 70% of synapses are associated with astrocyte processes, creating a three-point junction or tripartite synapse that enables tight communication between presynaptic and postsynaptic terminals and astrocyte processes. The main gliotransmitters released at tripartite synapses are glutamate and ATP.  Understanding vesicular-release, and the elaborate machinery in place that coordinates endocytosis, vesicle recycling, and calcium-dependent exocytosis, has been an enduring problem in neuroscience. Synergistic interactions between theorists and experimentalists have led to some of the most profound insights into neurotransmitter release machinery and organization.  One of the areas where there are several experimental results but no overarching theories is that of vesicle release by astrocytes in the hippocampus. Despite a decade of work, there are no detailed biophysical models that quantitatively investigate the effect of gliotransmitters released by astrocytes on neuronal activity. Our work attempts to fill some of these gaps in our understanding of astrocytic function. 

Energy/information balance during synaptic transmission  

Gaurang Mahajan 

The human brain makes up about 2% of the body weight but uses about 25% of the body's total energy budget. Within that, signal transmission at synapses alone is an energetically expensive process and consumes more than 50% of the brain's total energy. If every electrical impulse generated in the brain were transmitted to the connected synapses, the brain would need at least five times more energy than it already consumes. The CA3-CA1 synapse in the hippocampus is a crucial component of the neural circuit associated with learning. This synapse has a curiously low fidelity — Only 1 in 5 impulses are transmitted. The low transmission rate suggests a synaptic design that lowers energy consumption is favored. However, unreliable transmission can lead to a massive loss of information. We used information transmission and energy utilization, fundamental constraints that govern the neural organization, to gain insights into the relationship between the form and function of this synapse. We show that unreliable neurotransmitter release and its activity-dependent enhancement (short-term plasticity), a characterizing attribute of this synapse, maximizes information transmitted in an energetically cost-effective manner. Remarkably, our analysis reveals that synapse-specific quirks ensure information rate is independent of the release probability. Thus, even as ongoing long-term memory storage continues to fuel heterogeneity in synaptic strengths, individual synapses maintain robust information transmission.

Modeling APP oligomerization in hippocampal synapses 

Pratyush Ramakrishna (In collaboration with Dr. Deepak Nair, IISc)

We model the diffusion of Amyloid Precursor Protein (APP) and its breakdown into amyloid-beta in realistic synaptic geometries. Accumulation of amyloid-beta is thought to be the root cause of the cognitive decline in AD. 

Role of brain rhythms in health and disease

Rohan Sharma