Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
The amygdala, an almond-shaped structure in the midtemporal lobe, plays a central role in emotional behavior, as well as in modulating cognitive functions. Thus, the amygdala is a key component of the brain's neuronal networks that determine the emotional significance of external -and internal- events. Via reciprocal connections with the prefrontal cortex, the amygdala provides a neurobiological substrate through which emotions affect cognition (and vice versa). Via reciprocal connections with the hippocampus, as well as with other cortical and subcortical areas, the amygdala modulates memory functions, and mediates certain forms of memory. Furthermore, via efferent pathways to the hypothalamus, the amygdala can trigger the autonomic and endocrine cascades associated with the response to a stressful event. It is not surprising therefore, that many emotional/psychiatric disorders are associated with dysfunction of the amygdala. For example, anxiety disorders are associated with a hyperactive and/or hyperexcitable amygdala. One goal of the research program in our laboratory is to understand the mechanisms regulating neuronal excitability in the amygdala, and the alterations in these mechanisms in anxiety disorders. As the GABAergic and glutamatergic system are the primary determinants of neuronal excitability in the brain, we are using electrophysiological techniques (whole-cell patch-clamp, intracellular and field potential recordings), as well as molecular methods, to study the modulation of GABAergic and glutamatergic synaptic transmission in the amygdala of normal and fear-conditioned rats and mice. We also study plasticity of glutamatergic synaptic transmission (Long-Term Potentiation, LTP) in these animals, as LTP is considered to be the cellular mechanism for acquiring and consolidating information, and therefore alterations in synaptic plasticity can have a profound effect on the function of a brain region.
In addition to its role in emotional disorders, the amygdala also plays a central role in epilepsy. The basolateral nucleus of the amygdala (BLA), in particular, is highly prone to generating seizure activity, and, in many models of epilepsy, it is the focal point from where epileptic activity is spread to other brain areas, culminating in status epilepticus. The second research goal in our laboratory is to understand the role of the amygdala in epileptogenesis. Epileptogenesis is the process whereby, after an acute brain insult, such as traumatic brain injury, progressive pathophysiological alterations in neuronal networks occur that lead to the development of epilepsy. We recently identified an important mechanism regulating neuronal excitability and epileptic activity in BLA. We demonstrated that, in the rat BLA, kainate receptors containing the GluR5 subunit (GluR5KRs) regulate GABAergic inhibitory synaptic transmission via both postsynaptic and presynaptic mechanisms. The relevance of these findings to epilepsy is suggested by additional findings that a) activation of GluR5KRs can induce epileptiform activity in in vitro amygdala slices, and epilepsy in vivo, b) expression of these receptors is elevated in epileptic temporal lobe regions, in both humans and rats, c) GluR5-KRs are a primary target of a commonly used antiepileptic drug (topiramate), and d) GluR5-KR antagonists prevent limbic seizures. We are working on identifying the alterations in GABAergic and glutamatergic synaptic transmission, in the BLA, during the course of epileptogenesis, and determining whether changes in the function of GluR5KRs contribute to these alterations. We will also determine whether genetic elimination or pharmacological blockade of GluR5KRs can inhibit epileptogenesis. Unraveling the role of GluR5KRs in the pathogenesis of epilepsy may have significant implications for the discovery of antiepileptogenic drugs that have fewer side effects, as GluR5KR antagonist do not affect normal synaptic transmission and GluR5KRs are not widely distributed in the brain.
In summary, the goal of our research program is to provide the basic knowledge that is necessary for the development of effective therapeutic strategies aimed at preventing or treating certain neurological and psychiatric disorders where dysfunction of the amygdala plays a pivotal, causative role.